Transfer hydrogenation of cyclopamine analogs

ABSTRACT

Provided herein is a process for the transfer-hydrogenation of ketone analogs of members of the jervine type of  Veratrum  alkaloids, such as cyclopamine. Also provided herein are novel ruthenium transfer-hydrogenation catalysts.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/382,642, filed on Sep. 14, 2010, which is incorporated herein byreference in its entirety.

BACKGROUND

Cyclopamine, a natural product isolated from Veratrum californicum, hasemerged as a significant pharmacological tool to validate the Hedgehog(Hh) pathway in cancer. Cyclopamine directly acts on SMO and inhibitstumor growth in several murine models of pancreatic, medulloblastoma,prostate, small cell lung, and digestive tract cancers. However, theclinical development of cyclopamine as a therapeutic in cancer ishampered by its poor solubility, acid sensitivity, and weak potencyrelative to other reported small-molecule Hh antagonists.

There has been considerable focus on the development of novelcyclopamine analogues with improved potency, and improvedpharmacokinetic and pharmaceutical properties relative to cyclopamine(see, for example, U.S. Pat. Nos. 7,230,004 and 7,407,967, incorporatedherein by reference in its entirety). From that effort, a seven-memberedD-ring sulfonamide analogue of cyclopamine, IPI-926, emerged as aclinical development candidate (see, Tremblay et al., “Discovery of aPotent and Orally Active Hedgehog Pathway Antagonist (IPI-926)” J. Med.Chem. (2009) 52:4400-4418, incorporated herein by reference in itsentirety). Large quantities of IPI-926 are required for clinicaldevelopment. Moreover, other promising amino analogues can besynthesized following routes similar to that used to generate IPI-926.

In an exemplary approach to the synthesis of IPI-926, an intermediateketone (I-a) requires reduction to its corresponding alcohol (II-a) suchthat the IPI-926 sulfonamide substituent can be installed (see, FIG. 1).Known methods for ketone reduction on cyclopamine analogs such as (I-a)include, but are not limited to, the use of K-selectride as the reducingagent (see, e.g., Tremblay ibid.; U.S. Pat. No. 7,812,164, incorporatedherein by reference in its entirety). However, this reaction isexothermic and requires cryogenic temperatures (e.g., below −20° C.).Moreover, the exothermic oxidative work-up with hydrogen peroxide posessignificant challenges for pilot plant production. Thus, a milderreduction procedure with a more facile work-up for large scale reactionsis desirable.

SUMMARY

Provided herein is a process for the transfer-hydrogenation ofcyclopamine analogues. Also provided herein are novel rutheniumtransfer-hydrogenation catalysts.

For example, in one aspect, provided herein is a process for preparing acompound of formula (II):

or its pharmaceutically acceptable forms thereof;

from a compound of formula (I):

or its pharmaceutically acceptable forms thereof;

wherein:

R¹ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —OR¹⁶, —C(O)R¹⁶, —CO₂R¹⁶,—SO₂R¹⁶, —C(O)N(R¹⁷)(R¹⁷), —[C(R¹⁶)₂]_(q)—R¹⁶, —[(W)—N(R¹⁷)C(O)]_(q)R¹⁶,—[(W)—C(O)]_(q)R¹⁶, —[(W)—C(O)O]_(q)R¹⁶, —[(W)—OC(O)]_(q)R¹⁶,—[(W)—SO₂]_(q)R¹⁶, —[(W)—N(R¹⁷)SO₂]_(q)R¹⁶, —[(W)—C(O)N(R¹⁷)]_(q)R¹⁷,—[(W)—O]_(q)R¹⁶, —[(W)—N(R¹⁷)]_(q)R¹⁶, or —[(W)—S]_(q)R¹⁶; wherein W isa diradical and q is 1, 2, 3, 4, 5, or 6;

each R² and R³ is, independently, H, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl,haloalkyl, halo, —OR¹⁶, —OR¹⁶, —N(R¹⁷)₂, or —SR¹⁶, or R² and R³ takentogether form a double bond or form a group:

wherein Z is NR¹⁷, O, or C(R¹⁸)₂;

R⁴ is independently H, halo, —OR¹⁶, —N(R¹⁷)₂, or —SR¹⁶;

each R⁵ and R⁶, is, independently, H, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halo,—OR¹⁶, —N(R¹⁷)₂, or —SR¹⁶; or R⁵ and R⁶ taken together with the carbonto which they are bonded form C═O, C═S, C═N—OR¹⁷, C═N—R¹⁷, C═N—N(R¹⁷)₂,or form an optionally substituted 3-8 membered ring;

each R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹³ is, independently, H, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl,heteroaryl, heteroaralkyl, halo, —OR¹⁶, —N(R¹⁷)₂, or —SR¹⁶;

or R¹¹ and R¹² taken together, form a double bond;

or R¹⁰ and R¹¹ taken together, or R¹¹ and R¹² taken together, form agroup:

wherein Z is NR¹⁷, O, or C(R¹⁸)₂;

each R¹⁴ and R¹⁵ is independently, H, halo, —OR¹⁶, —N(R¹⁷)₂, or —SR¹⁶;or R¹⁴ and R¹⁵ taken together with the carbon to which they are bondedform C═O or C═S;

X is a bond or the group —C(R¹⁹)₂—, wherein each R¹⁹ is, independently,H, alkyl, aralkyl, halo, —CN, —OR¹⁶, or —N(R¹⁷)₂;

R¹⁶ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, heteroaralkyl or) —[C(R²⁰)₂]_(p)—R²¹ wherein p is0-6; or any two occurrences of R¹⁶ on the same substituent are takentogether to form a 4-8 membered optionally substituted ring;

R¹⁷ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, heteroaralkyl, —C(═O)R²⁰, —C(═O)OR²⁰, —SO₂R²⁰,—C(═O)N(R²⁰)₂, or —[C(R²⁰)₂]_(p)—R²¹ wherein p is 0-6; or any twooccurrences of R¹⁷ on the same substituent are taken together to form a4-8 membered optionally substituted ring;

R¹⁸ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, heteroaralkyl, halo, —CN, —OR²⁰, —OSi(R²⁰)₃,—C(═O)R²⁰, —C(═O)OR²⁰, —SO₂R²⁰ or —C(═O)N(R²⁰)₂;

R²⁰ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, or heteroaralkyl; or any two occurrences of R²⁰ onthe same substituent are taken together to form a 4-8 memberedoptionally substituted ring;

R²¹ is —OR²², —N(R²²)C(═O)R²², —N(R²²)C(═O)OR²², —N(R²²)SO₂(R²²),—C(═O)R²²N(R²²)₂, —OC(═O)R²²N(R²²)(R²²), —SO₂N(R²²)(R²²), —N(R²²)(R²²),—C(═O)OR²², —C(═O)N(OH)(R²²), —OS(O)₂OR²², —S(O)₂OR²²,—OP(═O)(OR²²)(OR²²), —N(R²²)P(O)(OR²²)(OR²²), or —P(═O)(OR²²)(OR²²); and

R²² is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, heteroaralkyl; or any two occurrences of R²² on thesame substituent are taken together to form a 4-8 membered optionallysubstituted ring;

the process comprising reacting a compound of formula (I) or itspharmaceutically acceptable forms thereof with a transfer-hydrogenationcatalyst in order to provide a compound of formula (II) or itspharmaceutically acceptable forms thereof.

In certain embodiments, the process preferentially generates a compoundof formula (II), or its pharmaceutically acceptable forms thereof,wherein the newly-formed hydroxyl group has the β (beta) orientation,meaning that the newly-formed hydroxyl group is above the plane of thering in formula (II). In these embodiments, the bond between thenewly-formed hydroxyl group and the ring carbon atom to which the newlyformed hydroxyl group is attached is shown as a solid line (e.g.

,

, and the like).

In other embodiments, the process generates a compound of formula (II),or its pharmaceutically acceptable forms thereof, wherein thenewly-formed hydroxyl group has the α (alpha) orientation, meaning thatthe newly-formed hydroxyl group is below the plane of the ring informula (II). In these embodiments, the bond between the newly-formedhydroxyl group and the ring carbon atom to which the newly formedhydroxyl group is attached is shown as a dashed line (e.g.

, ----- , and the like).

In certain embodiments, the process preferentially generates a compoundof formula (II), or its pharmaceutically acceptable forms thereof,wherein the carbon atom that is directly attached to the newly-formedhydroxyl group has the (S) configuration.

In other embodiments, the process generates a compound of formula (II),or its pharmaceutically acceptable forms thereof, wherein the carbonatom that is directly attached to the newly-formed hydroxyl group hasthe (R) configuration.

In certain embodiments, the process preferentially generates a compoundof formula (II), or its pharmaceutically acceptable forms thereof,wherein the newly-formed hydroxyl group has the β (beta) orientation,and the carbon atom that is directly attached to the newly-formedhydroxyl group has the (S) configuration.

In certain embodiments, the process generates a compound of formula(II), or its pharmaceutically acceptable forms thereof, wherein thenewly-formed hydroxyl group has the β (beta) orientation, and the carbonatom that is directly attached to the newly-formed hydroxyl group hasthe (R) configuration.

In other embodiments, the process generates a compound of formula (II),or its pharmaceutically acceptable forms thereof, wherein thenewly-formed hydroxyl group has the α (alpha) orientation, and thecarbon atom that is directly attached to the newly-formed hydroxyl grouphas the (R) configuration.

In other embodiments, the process generates a compound of formula (II),or its pharmaceutically acceptable forms thereof, wherein thenewly-formed hydroxyl group has the α (alpha) orientation, and thecarbon atom that is directly attached to the newly-formed hydroxyl grouphas the (S) configuration.

For example, in one aspect, provided herein is a process for preparing acompound of formula (II):

or its pharmaceutically acceptable forms thereof;from a compound of formula (I):

or its pharmaceutically acceptable forms thereof;wherein:

R¹ is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, heteroaralkyl, haloalkyl, heteroalkyl, —C(O)R¹⁶,—CO₂R¹⁶, —SO₂R¹⁶, —C(O)N(R¹⁷)(R¹⁷), —[C(R²³)₂]_(q)—R²³,—[(W)—N(R¹⁷)C(O)]_(q)R¹⁶, —[(W)—C(O)N(R¹⁷)]_(q)R¹⁷,—[(W)—N(R¹⁷)]_(q)R¹⁶, or —[(W)—S]_(q)R¹⁶; wherein W is (CH₂)_(q) andeach q is independently 1, 2, 3, 4, 5, or 6;

each R² and R³ is, independently, H, alkyl, alkenyl, alkynyl, aralkyl,heteroaralkyl, haloalkyl, heteroalkyl, CN, NO₂, halo, —OR¹⁶, —N(R¹⁷)₂,or —SR¹⁶, or R² and R³ taken together form a double bond or form agroup:

wherein Z is NR¹⁷, O, or C(R¹⁸)₂;

R⁴ is H, halo, —OR¹⁶, —N(R¹⁷)₂, or —SR¹⁶;

each R⁵ and R⁶, is, independently, H, alkyl, alkenyl, alkynyl, aralkyl,heteroaralkyl, heteroalkyl; or R⁵ and R⁶ taken together with the carbonto which they are bonded form C═O or C═S;

each R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ is, independently, H, alkyl,alkenyl, alkynyl, aralkyl, heteroaralkyl, heteroalkyl, halo, or —OR¹⁶,or R¹¹ and R¹² taken together, form a double bond;

each R¹⁴ and R¹⁵ is, independently, H, alkyl, alkenyl, alkynyl, aralkyl,heteroaralkyl, heteroalkyl, halo, —OR¹⁶, —N(R¹⁷)₂, or —SR¹⁶; or R¹⁴ andR¹⁵ taken together with the carbon to which they are bonded form C═O orC═S;

X is a bond or the group —C(R¹⁹)₂—, wherein each R¹⁹ is, independently,H, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, heteroalkyl, halo,—CN, —NO₂, —OR¹⁶, or —N(R¹⁷)₂;

R¹⁶ is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, or heteroaralkyl; or any two occurrences of R¹⁶ onthe same substituent are taken together to form a 4-8 memberedoptionally substituted ring;

R¹⁷ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, heteroaralkyl, —C(═O)R²⁰, —C(═O)OR²⁰, —SO₂R²⁰, or—C(═O)N(R²⁰)₂; or any two occurrences of R¹⁷ on the same substituent aretaken together to form a 4-8 membered optionally substituted ring;

R¹⁸ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, heteroaralkyl, heteroalkyl, halo, —CN, —OR²⁰,—OSi(R²⁰)₃, —N(R¹⁷)₂, —C(═O)R²⁰, —C(═O)OR²⁰, —SO₂R²⁰ or —C(═O)N(R²⁰)₂;

R²⁰ is H, H alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, or heteroaralkyl; or any two occurrences of R²⁰ onthe same substituent are taken together to form a 4-8 memberedoptionally substituted ring; and

R²³ is H, alkyl, alkenyl, alkynyl, amido, or amino;

the process comprising reacting a compound of formula (I) or itspharmaceutically acceptable forms thereof with a transfer-hydrogenationcatalyst in order to provide a compound of formula (II) or itspharmaceutically acceptable forms thereof.

For example, in one aspect, provided herein is a process for preparing acompound of formula (II):

or its pharmaceutically acceptable forms thereof;

from a compound of formula (I):

or its pharmaceutically acceptable forms thereof;

wherein:

R¹ is alkyl, alkenyl, alkynyl, aralkyl, —C(O)R¹⁶, —CO₂R¹⁶, —SO₂R¹⁶,—[C(R²³)₂]_(q)—R²³, —[(W)—N(R¹⁷)C(O)]_(q)R¹⁶, —[(W)—C(O)N(R¹⁷)]_(q)R¹⁷,or —[(W)—N(R¹⁷)]_(q)R¹⁶, W is (CH₂)_(q) and each q is independently 1,2, 3, 4, 5, or 6;

R⁵ and R⁶ are each H, or R⁵ and R⁶ taken together with the carbon towhich they are bonded form C═O;

R¹¹ and R¹² are each H (e.g., R¹¹ is hydrogen in the α or β-position),or R¹¹ and R¹² taken together form a double bond;

X is a bond or the group —CH₂—;

R¹⁶ is alkyl, alkenyl, alkynyl, aralkyl, alkoxy, arylalkoxy, orheteroaralkyl;

R¹⁷ is H, alkyl, alkenyl, or alkynyl; and

R²³ is H, alkyl, alkenyl, alkynyl, amido, or amino;

the process comprising reacting a compound of formula (I) or itspharmaceutically acceptable forms thereof with a transfer-hydrogenationcatalyst in order to provide a compound of formula (II) or itspharmaceutically acceptable forms thereof.

In certain embodiments, the compound of formula (I) is a compound offormula (I-a):

or its pharmaceutically acceptable forms thereof,

and the compound of formula (II) is a compound of formula (S)-(II-a):

or its pharmaceutically acceptable forms thereof.

In certain embodiments, the transfer-hydrogenation catalyst is aruthenium transfer-hydrogenation catalyst.

In certain embodiments, the ruthenium transfer-hydrogenation catalystcomprises an amino alcohol ligand.

In certain embodiments, the amino alcohol ligand is of the formula(i-a):

or its pharmaceutically acceptable forms thereof,

wherein each R^(a) and R^(b) are independently selected from hydrogen,alkyl, perhaloalkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl,heteroaryl, aralkyl, or heteroaralkyl, or R^(a) and R^(b) are joined toform a 3-8 membered carbocyclic or heterocyclic ring system;

and R^(c) is selected from alkyl, perhaloalkyl, alkenyl, alkynyl,carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl.

In certain embodiments, each R^(a) and R^(b) are independently selectedfrom C₁₋₆ alkyl and C₁₋₆ perhaloalkyl. In certain embodiments, eachR^(a) and R^(b) are independently selected from C₁₋₆ alkyl. In certainembodiments, each R^(a) and R^(b) are methyl.

In certain embodiments, R^(c) is C₁₋₆ alkyl. In certain embodiments,R^(c) is C₁₋₃ alkyl. In certain embodiments, R^(c) is —CH₂CH₃.

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isan achiral ruthenium transfer-hydrogenation catalyst.

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isan achiral ruthenium transfer-hydrogenation catalyst comprising an aminoalcohol ligand of the formula (i-a) where R^(a) and R^(b) are the samegroup. For example, in certain embodiments, R^(a) and R^(b) are the samegroup selected from C₁₋₆ alkyl and C₁₋₆ perhaloalkyl. In certainembodiments, R^(a) and R^(b) are the same group selected from C₁₋₆alkyl. In certain embodiments, R^(a) and R^(b) are both —CH₃.

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isa chiral ruthenium transfer-hydrogenation catalyst.

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isa chiral ruthenium transfer-hydrogenation catalyst comprising an aminoalcohol ligand of the formula (i-a). For example, in certainembodiments, R^(a) is hydrogen and R^(b) is C₁₋₆ alkyl, or R^(b) ishydrogen and R^(a) is C₁₋₆ alkyl. In certain embodiments, R^(a) ishydrogen and R^(b) is C₁₋₆ alkyl, or R^(b) is hydrogen and R^(a) is C₁₋₆alkyl.

In certain embodiments, the amino alcohol ligand is of the formula(i-b):

In certain embodiments, the amino alcohol ligand is of the formula(i-c):

In certain embodiments, the amino alcohol ligand is of the formula(i-i):

In certain embodiments, the amino alcohol ligand is of the formula(i-j):

In some embodiments, the amino alcohol ligand is of Formula (i-z):

or its pharmaceutically acceptable forms thereof,

wherein each R^(a) and R^(b) are independently selected from hydrogen,alkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, or R^(a)and R^(b) are joined to form a 3-10 membered carbocyclic or heterocyclicring system;

each R^(n) and R^(o) are independently selected from hydrogen, alkyl,perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, or R^(n)and R^(o) are joined to form a 3-10 membered carbocyclic or heterocyclicring system; or

R^(a) and R^(n) are joined together to form a 3-10 membered carbocyclicor heterocyclic ring system and R^(b) and R^(o) are each hydrogen; or

R^(a) and R^(o) are joined together to form a 3-10 membered carbocyclicor heterocyclic ring system and R^(b) and R^(n) are each hydrogen; or

R^(b) and R^(o) are joined together to form a 3-10 membered carbocyclicor heterocyclic ring system and R^(a) and R^(n) are each hydrogen; or

R^(b) and R^(n) are joined together to form a 3-10 membered carbocyclicor heterocyclic ring system and R^(a) and R^(o) are each hydrogen; and

R^(c) is selected from alkyl, perhaloalkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl,and heteroaralkyl; or

R^(a) and R^(c) are joined together to form a 3-10 membered carbocyclicor heterocyclic ring system and R^(b) is hydrogen; or

R^(b) and R^(c) are joined together to form a 3-10 membered carbocyclicor heterocyclic ring system and R^(a) is hydrogen.

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isa chiral ruthenium transfer-hydrogenation catalyst comprising an aminoalcohol ligand of the formula (i-z). For example, in certainembodiments, R^(a) is hydrogen and R^(b) is C₁₋₆ alkyl, or R^(b) ishydrogen and R^(a) is C₁₋₆ alkyl. In certain embodiments, R^(a) ishydrogen and R^(b) is Me, or R^(b) is hydrogen and R^(a) is Me. Incertain embodiments, R^(n) is aryl and R^(o) is hydrogen, or R^(o) ishydrogen and R^(n) is aryl. In certain embodiments, R^(n) is phenyl andR^(o) is hydrogen, or R^(o) is hydrogen and R^(n) is phenyl.

In certain embodiments, the ruthenium transfer-hydrogenation catalystfurther comprises an optionally substituted benzene ligand. In certainembodiments, the optionally substituted benzene ligand ishexamethylbenzene.

In certain embodiments, the ruthenium transfer-hydrogenation catalystfurther comprises a halo ligand. In certain embodiments, the halo ligandis chloro.

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isgenerated from hexamethylbenzene ruthenium chloride dimer and an aminoalcohol.

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isan achiral catalyst of the formula (iii-a):

wherein:

each R^(a) and R^(b) are the same group selected from hydrogen, alkyl,perhaloalkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl,heteroaryl, aralkyl, or heteroaralkyl, or R^(a) and R^(b) are joined toform a 3-8 membered carbocyclic or heterocyclic ring system;

R^(c) is selected from alkyl, perhaloalkyl, alkenyl, alkynyl,carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl;and

each R^(h), R^(i), R^(j), R^(k), R^(l), and R^(m) are independentlyselected from hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl,carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl.

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isof the formula (iii-b):

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isof the formula (iii-c):

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isof the formula (iii-d):

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isof the formula (iii-g):

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isof the formula (iii-h):

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isa chiral ruthenium transfer-hydrogenation catalyst selected fromCl3[((R)-tol-BINAP)RuCl]2-Me2NH2+, Cl3[((S)-tol-BINAP)RuCl]2-Me2NH2+,((R)-DIFLUORPHOS)RuCl2(DMF)n, ((S)-DIFLUORPHOS)RuCl2(DMF)n,((R)-DTBM-SEGPHOS)RuCl2(p-cymene), ((S)-DTBM-SEGPHOS)RuCl2(p-cymene),Cl3[((R)-xylyl-SEGPHOS)RuCl]2-Me2NH2+,Cl3[((S)-xylyl-SEGPHOS)RuCl]2-Me2NH2+,((R)-xylyl-SEGPHOS)RuCl2(R,R)DPEN, ((S)-xylyl-SEGPHOS)RuCl2(S,S)DPEN,(Ph3P)RuCl2((+)-(R)—Fe-oxazoline), (Ph3P)RuCl2((−)-(S)—Fe-oxazoline),((S,R)JOSIPHOS)RuCl2(DMF)n, ((R,S)JOSIPHOS)RuCl2(DMF)n,(11bS,11′bS)-4,4′-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis-dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepineand its enantiomer, (S,S)TsDPEN-RuCl(p-cymene),(S,S)TsDPEN-RuCl(hexamethylbenzene),(S,S)TsCyDN-RuCl(hexamethylbenzene),RuHCl(mesitylene)[(1S,2R)-ephedrine],RuHCl(hexamethylbenzene)[(1S,2R)-ephedrine],RuHCl(hexamethylbenzene)[(1R,2S)-ephedrine],RuHCl(p-cymene)[(1S,2R)-ephedrine], RuHCl(p-cymene)[(1R,2S)-ephedrine],RuHCl(benzene)[(1S,2R)-ephedrine],RuHCl(mesitylene)[(1R,2S)-2-methylaminocyclohexanol],RuHCl(hexamethylbenzene) [(1R,2S)-2-methylaminocyclohexanol],RuHCl(hexamethylbenzene)[(1S,2S)-2-methylaminocyclohexanol],RuHCl(p-cymene)[(1R,2S)-2-methylaminocyclohexanol], andRuHCl(benzene)[(1R,2S)-2-methylaminocyclohexanol],RuHCl(hexamethylbenzene)[R-propranolol],RuHCl(hexamethylbenzene)[S-propranolol],RuHCl(hexamethylbenzene)[1R,2S-cis-1-amino-2-indanol], andRuHCl(hexamethylbenzene)[D-prolinol].

Also provided herein is a catalyst of the formula (iii-a):

wherein R^(a) and R^(b) are the same group selected from C₁₋₆ alkyl andC₁₋₆ perhaloalkyl, or R^(a) and R^(b) are joined to form a 3-8 memberedcarbocyclic or heterocyclic ring system;

R^(c) is selected from C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, aralkyl,heteroaralkyl, aryl and heteroaryl; and

each R^(h), R^(i), R^(j), R^(k), R^(l), and R^(m) are independentlyselected from hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl,carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl.

Also provided herein is a catalyst of the formula (iii-h):

wherein each R^(a), R^(b), R^(n) and R^(o) are independently selectedfrom hydrogen, alkyl, aryloxyalkyl, aryl, and perhaloalkyl, or

R^(a) and R^(n) are joined together to form a 3-10 membered carbocyclicor heterocyclic ring system and R^(b) and R^(o) are each hydrogen; or

R^(a) and R^(o) are joined together to form a 3-10 membered carbocyclicor heterocyclic ring system and R^(b) and R^(n) are each hydrogen; or

R^(b) and R^(o) are joined together to form a 3-10 membered carbocyclicor heterocyclic ring system and R^(a) and R^(n) are each hydrogen; or

R^(b) and R^(n) are joined together to form a 3-10 membered carbocyclicor heterocyclic ring system and R^(a) and R^(o) are each hydrogen; and

R^(c) is selected from C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, aralkyl,heteroaralkyl, aryl and heteroaryl; and

each R^(h), R^(i), R^(j), R^(k), R^(l), and R^(m) are independentlyselected from hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl,carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl.

The details of additional or alternative embodiments are set forth inthe accompanying Detailed Description and Exemplification as describedbelow. Other features, objects, and advantages of the invention will beapparent from this description and from the claims.

DEFINITIONS

While specific embodiments have been discussed, the specification isillustrative only and not restrictive. Many variations of thisdisclosure will become apparent to those skilled in the art upon reviewof this specification.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this specification pertains.

As used in the specification and claims, the singular form “a”, “an” and“the” includes plural references unless the context clearly dictatesotherwise.

Definitions of specific functional groups and chemical terms aredescribed in more detail below. For purposes of this invention, thechemical elements are identified in accordance with the Periodic Tableof the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th)Ed., inside cover, and specific functional groups are generally definedas described therein. Additionally, general principles of organicchemistry, as well as specific functional moieties and reactivity, aredescribed in, for example, Organic Chemistry, Thomas Sorrell, UniversityScience Books, Sausalito, 1999; Smith and March March's Advanced OrganicChemistry, 5^(th) Edition, John Wiley & Sons, Inc., New York, 2001;Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., NewYork, 1989; and Carruthers, Some Modern Methods of Organic Synthesis,3^(rd) Edition, Cambridge University Press, Cambridge, 1987.

As used herein, a “pharmaceutically acceptable form” of a disclosedcompound includes, but is not limited to, pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives of disclosed compounds.

In certain embodiments, the pharmaceutically acceptable form is apharmaceutically acceptable salt. As used herein, the term“pharmaceutically acceptable salt” refers to those salts which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of subjects without undue toxicity, irritation,allergic response and the like, and are commensurate with a reasonablebenefit/risk ratio. Pharmaceutically acceptable salts are well known inthe art. For example, Berge et al. describes pharmaceutically acceptablesalts in detail in J. Pharmaceutical Sciences (1977) 66:1-19.Pharmaceutically acceptable salts of the compounds provided hereininclude those derived from suitable inorganic and organic acids andbases. Examples of pharmaceutically acceptable, nontoxic acid additionsalts are salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. In some embodiments, organic acids from which salts can bederived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like.

Pharmaceutically acceptable salts derived from appropriate bases includealkali metal, alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)⁴-salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate. Organic bases from which salts can be derived include, forexample, primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines, basicion exchange resins, and the like, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. In some embodiments, the pharmaceutically acceptable baseaddition salt is chosen from ammonium, potassium, sodium, calcium, andmagnesium salts.

In certain embodiments, the pharmaceutically acceptable form is a“solvate” (e.g., a hydrate). As used herein, the term “solvate” refersto compounds that further include a stoichiometric or non-stoichiometricamount of solvent bound by non-covalent intermolecular forces. Thesolvate can be of a disclosed compound or a pharmaceutically acceptablesalt thereof. Where the solvent is water, the solvate is a “hydrate”.Pharmaceutically acceptable solvates and hydrates are complexes that,for example, can include 1 to about 100, or 1 to about 10, or one toabout 2, 3 or 4, solvent or water molecules. It will be understood thatthe term “compound” as used herein encompasses the compound and solvatesof the compound, as well as mixtures thereof.

In certain embodiments, the pharmaceutically acceptable form is aprodrug. As used herein, the term “prodrug” refers to compounds that aretransformed in vivo to yield a disclosed compound or a pharmaceuticallyacceptable form of the compound. A prodrug can be inactive whenadministered to a subject, but is converted in vivo to an activecompound, for example, by hydrolysis (e.g., hydrolysis in blood). Incertain cases, a prodrug has improved physical and/or deliveryproperties over the parent compound. Prodrugs are typically designed toenhance pharmaceutically and/or pharmacokinetically based propertiesassociated with the parent compound. The prodrug compound often offersadvantages of solubility, tissue compatibility or delayed release in amammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985),pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs isprovided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,”A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated in full byreference herein. Exemplary advantages of a prodrug can include, but arenot limited to, its physical properties, such as enhanced watersolubility for parenteral administration at physiological pH compared tothe parent compound, or it enhances absorption from the digestive tract,or it can enhance drug stability for long-term storage.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a subject. Prodrugs of an active compound, as describedherein, can be prepared by modifying functional groups present in theactive compound in such a way that the modifications are cleaved, eitherin routine manipulation or in vivo, to the parent active compound.Prodrugs include compounds wherein a hydroxy, amino or mercapto group isbonded to any group that, when the prodrug of the active compound isadministered to a subject, cleaves to form a free hydroxy, free amino orfree mercapto group, respectively. Examples of prodrugs include, but arenot limited to, acetate, formate and benzoate derivatives of an alcoholor acetamide, formamide and benzamide derivatives of an amine functionalgroup in the active compound and the like. Other examples of prodrugsinclude compounds that comprise —NO, —NO₂, —ONO, or —ONO₂ moieties.Prodrugs can typically be prepared using well-known methods, such asthose described in Burger's Medicinal Chemistry and Drug Discovery,172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995), and Design ofProdrugs (H. Bundgaard ed., Elselvier, New York, 1985).

For example, if a disclosed compound or a pharmaceutically acceptableform of the compound contains a carboxylic acid functional group, aprodrug can comprise a pharmaceutically acceptable ester formed by thereplacement of the hydrogen atom of the acid group with a group such as(C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl havingfrom 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbonatoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms;3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as (3-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Similarly, if a disclosed compound or a pharmaceutically acceptable formof the compound contains an alcohol functional group, a prodrug can beformed by the replacement of the hydrogen atom of the alcohol group witha group such as (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl(C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate).

If a disclosed compound or a pharmaceutically acceptable form of thecompound incorporates an amine functional group, a prodrug can be formedby the replacement of a hydrogen atom in the amine group with a groupsuch as R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are eachindependently (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, benzyl, a naturalα-aminoacyl or natural α-aminoacyl-natural α-aminoacyl, —C(OH)C(O)OY¹wherein Y¹ is H, (C₁-C₆)alkyl or benzyl, —C(OY²)Y³ wherein Y² is(C₁-C₄)alkyl and Y³ is (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,amino(C₁-C₄)alkyl or mono-N— or di-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵wherein Y⁴ is H or methyl and Y⁵ is mono-N— or di-N,N—(C₁-C₆)alkylamino,morpholino, piperidin-1-yl or pyrrolidin-1-yl.

In certain embodiments, the pharmaceutically acceptable form is anisomer. “Isomers” are different compounds that have the same molecularformula. “Stereoisomers” are isomers that differ only in the way theatoms are arranged in space. As used herein, the term “isomer” includesany and all geometric isomers and stereoisomers. For example, “isomers”include geometric double bond cis- and trans-isomers, also termed E- andZ-isomers; R- and S-enantiomers; diastereomers, (d)-isomers and(l)-isomers, racemic mixtures thereof; and other mixtures thereof, asfalling within the scope of this disclosure.

Geometric isomers can be represented by the symbol

which denotes a bond that can be a single, double or triple bond asdescribed herein. Provided herein are various geometric isomers andmixtures thereof resulting from the arrangement of substituents around acarbon-carbon double bond or arrangement of substituents around acarbocyclic ring. Substituents around a carbon-carbon double bond aredesignated as being in the “Z” or “E” configuration wherein the terms“Z” and “E” are used in accordance with IUPAC standards. Unlessotherwise specified, structures depicting double bonds encompass boththe “E” and “Z” isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangement of substituentsaround a carbocyclic ring can also be designated as “cis” or “trans.”The term “cis” represents substituents on the same side of the plane ofthe ring, and the term “trans” represents substituents on opposite sidesof the plane of the ring. Mixtures of compounds wherein the substituentsare disposed on both the same and opposite sides of plane of the ringare designated “cis/trans.”

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A mixture of a pair of enantiomers in anyproportion can be known as a “racemic” mixture. The term “(±)” is usedto designate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is anenantiomer, the stereochemistry at each chiral carbon can be specifiedby either R or S. Resolved compounds whose absolute configuration isunknown can be designated (+) or (−) depending on the direction (dextro-or levorotatory) which they rotate plane polarized light at thewavelength of the sodium D line. Certain of the compounds describedherein contain one or more asymmetric centers and can thus give rise toenantiomers, diastereomers, and other stereoisomeric forms that can bedefined, in terms of absolute stereochemistry at each asymmetric atom,as (R)- or (S)-. The chemical entities, pharmaceutical compositions andmethods described herein are meant to include all such possible isomers,including racemic mixtures, optically substantially pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers can beprepared, for example, using chiral synthons or chiral reagents, orresolved using conventional techniques.

The “enantiomeric excess” or “% enantiomeric excess” of a compositioncan be calculated using the equation shown below. In the example shownbelow, a composition contains 90% of one enantiomer, e.g., the Senantiomer, and 10% of the other enantiomer, e.g., the R enantiomer.ee=(90−10)/100=80%

Thus, a composition containing 90% of one enantiomer and 10% of theother enantiomer is said to have an enantiomeric excess of 80%. Somecompositions described herein contain an enantiomeric excess of at leastabout 50%, 75%, 90%, 95%, or 99% of the S enantiomer. In other words,the compositions contain an enantiomeric excess of the S enantiomer overthe R enantiomer. In other embodiments, some compositions describedherein contain an enantiomeric excess of at least about 50%, 75%, 90%,95%, or 99% of the R enantiomer. In other words, the compositionscontain an enantiomeric excess of the R enantiomer over the Senantiomer.

For instance, an isomer/enantiomer can, in some embodiments, be providedsubstantially free of the corresponding isomer/enantiomer, and can alsobe referred to as “optically enriched,” “enantiomerically enriched,”“enantiomerically pure” and “non-racemic,” as used interchangeablyherein. These terms refer to compositions in which the percent by weightof one enantiomer is greater than the amount of that one enantiomer in acontrol mixture of the racemic composition (e.g., greater than 1:1 byweight). For example, an enantiomerically enriched preparation of the Senantiomer, means a preparation of the compound having greater thanabout 50% by weight of the S enantiomer relative to the R enantiomer,such as at least about 75% by weight, further such as at least about 80%by weight. In some embodiments, the enrichment can be much greater thanabout 80% by weight, providing a “substantially enantiomericallyenriched,” “substantially enantiomerically pure” or a “substantiallynon-racemic” preparation, which refers to preparations of compositionswhich have at least about 85% by weight of one enantiomer relative toother enantiomer, such as at least about 90% by weight, and further suchas at least 95% by weight. In certain embodiments, the compound providedherein is made up of at least about 90% by weight of one enantiomer. Inother embodiments, the compound is made up of at least about 95%, 98%,or 99% by weight of one enantiomer.

In some embodiments, the compound is a racemic mixture of (S)- and(R)-isomers. In other embodiments, provided herein is a mixture ofcompounds wherein individual compounds of the mixture existpredominately in an (S)- or (R)-isomeric configuration. For example, thecompound mixture has an (S)-enantiomeric excess of greater than about55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%,about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about99.5%, or more. In other embodiments, the compound mixture has an(S)-enantiomeric excess of greater than about 55% to about 99.5%,greater than about 60% to about 99.5%, greater than about 65% to about99.5%, greater than about 70% to about 99.5%, greater than about 75% toabout 99.5%, greater than about 80% to about 99.5%, greater than about85% to about 99.5%, greater than about 90% to about 99.5%, greater thanabout 95% to about 99.5%, greater than about 96% to about 99.5%, greaterthan about 97% to about 99.5%, greater than about 98% to greater thanabout 99.5%, greater than about 99% to about 99.5%, or more.

In other embodiments, the compound mixture has an (R)-enantiomericpurity of greater than about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%,about 98%, about 99%, about 99.5% or more. In some other embodiments,the compound mixture has an (R)-enantiomeric excess of greater thanabout 55% to about 99.5%, greater than about 60% to about 99.5%, greaterthan about 65% to about 99.5%, greater than about 70% to about 99.5%,greater than about 75% to about 99.5%, greater than about 80% to about99.5%, greater than about 85% to about 99.5%, greater than about 90% toabout 99.5%, greater than about 95% to about 99.5%, greater than about96% to about 99.5%, greater than about 97% to about 99.5%, greater thanabout 98% to greater than about 99.5%, greater than about 99% to about99.5% or more.

In other embodiments, the compound mixture contains identical chemicalentities except for their stereochemical orientations, namely (S)- or(R)-isomers. For example, if a compound disclosed herein has —CH(R)—unit, and R is not hydrogen, then the —CH(R)— is in an (S)- or(R)-stereochemical orientation for each of the identical chemicalentities. In some embodiments, the mixture of identical chemicalentities is a racemic mixture of (S)- and (R)-isomers. In anotherembodiment, the mixture of the identical chemical entities (except fortheir stereochemical orientations), contain predominately (S)-isomers orpredominately (R)-isomers. For example, the (S)-isomers in the mixtureof identical chemical entities are present at about 55%, about 60%,about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more,relative to the (R)-isomers. In some embodiments, the (S)-isomers in themixture of identical chemical entities are present at an(S)-enantiomeric excess of greater than about 55% to about 99.5%,greater than about 60% to about 99.5%, greater than about 65% to about99.5%, greater than about 70% to about 99.5%, greater than about 75% toabout 99.5%, greater than about 80% to about 99.5%, greater than about85% to about 99.5%, greater than about 90% to about 99.5%, greater thanabout 95% to about 99.5%, greater than about 96% to about 99.5%, greaterthan about 97% to about 99.5%, greater than about 98% to greater thanabout 99.5%, greater than about 99% to about 99.5% or more.

In another embodiment, the (R)-isomers in the mixture of identicalchemical entities (except for their stereochemical orientations), arepresent at about 55%, about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%,about 99%, about 99.5%, or more, relative to the (S)-isomers. In someembodiments, the (R)-isomers in the mixture of identical chemicalentities (except for their stereochemical orientations), are present ata (R)-enantiomeric excess greater than about 55% to about 99.5%, greaterthan about 60% to about 99.5%, greater than about 65% to about 99.5%,greater than about 70% to about 99.5%, greater than about 75% to about99.5%, greater than about 80% to about 99.5%, greater than about 85% toabout 99.5%, greater than about 90% to about 99.5%, greater than about95% to about 99.5%, greater than about 96% to about 99.5%, greater thanabout 97% to about 99.5%, greater than about 98% to greater than about99.5%, greater than about 99% to about 99.5%, or more.

Enantiomers can be isolated from racemic mixtures by any method known tothose skilled in the art, including chiral high pressure liquidchromatography (HPLC), the formation and crystallization of chiralsalts, or prepared by asymmetric syntheses. See, for example,Enantiomers, Racemates and Resolutions (Jacques, Ed., WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977);Stereochemistry of Carbon Compounds (E. L. Eliel, Ed., McGraw-Hill, NewYork, 1962); and Tables of Resolving Agents and Optical Resolutions p.268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind.1972).

The term “asymmetric center” refers to a tetrahedral carbon atomsubstituted by four different groups. The term “chiral” refers to amolecule or complex having at least one asymmetric center, or otherwiselacking an internal plane or center of symmetry, and thus having anon-superimposable mirror image. In certain embodiments, the term“chiral” refers to a molecule or complex having at least one asymmetriccenter. The term “achiral” refers to a molecule or complex having atleast one of a plane of symmetry or a center of symmetry. In certainembodiments, the term “achiral” refers to a molecule or complex havingno asymmetric centers.

In certain embodiments, the pharmaceutically acceptable form is atautomer. As used herein, the term “tautomer” is a type of isomer thatincludes two or more interconvertable compounds resulting from at leastone formal migration of a hydrogen atom and at least one change invalency (e.g., a single bond to a double bond, a triple bond to a singlebond, or vice versa). “Tautomerization” includes prototropic orproton-shift tautomerization, which is considered a subset of acid-basechemistry. “Prototropic tautomerization” or “proton-shifttautomerization” involves the migration of a proton accompanied bychanges in bond order. The exact ratio of the tautomers depends onseveral factors, including temperature, solvent, and pH. Wheretautomerization is possible (e.g., in solution), a chemical equilibriumof tautomers can be reached. Tautomerizations (i.e., the reactionproviding a tautomeric pair) can be catalyzed by acid or base, or canoccur without the action or presence of an external agent. Exemplarytautomerizations include, but are not limited to, keto-to-enol;amide-to-imide; lactam-to-lactim; enamine-to-imine; and enamine-to-(adifferent) enamine tautomerizations. A specific example of keto-enoltautomerization is the interconversion of pentane-2,4-dione and4-hydroxypent-3-en-2-one tautomers. Another example of tautomerizationis phenol-keto tautomerization. A specific example of phenol-ketotautomerization is the interconversion of pyridin-4-ol andpyridin-4(1H)-one tautomers.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this disclosure.

The disclosure also embraces isotopically labeled compounds which areidentical to those recited herein, except that one or more atoms arereplaced by an atom having an atomic mass or mass number different fromthe atomic mass or mass number usually found in nature. Examples ofisotopes that can be incorporated into disclosed compounds includeisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine andchlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F,and ³⁶Cl, respectively. Certain isotopically-labeled disclosed compounds(e.g., those labeled with ³H and ¹⁴C) are useful in compound and/orsubstrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14(i.e., ¹⁴C) isotopes can allow for ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) can afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements). Isotopically labeled disclosed compoundscan generally be prepared by substituting an isotopically labeledreagent for a non-isotopically labeled reagent. In some embodiments,provided herein are compounds that can also contain unnaturalproportions of atomic isotopes at one or more of atoms that constitutesuch compounds. All isotopic variations of the compounds as disclosedherein, whether radioactive or not, are encompassed within the scope ofthe present disclosure.

Carbon atoms, unless otherwise specified, may optionally be substitutedwith one or more substituents. The number of substituents is typicallylimited by the number of available valences on the carbon atom, and maybe substituted by replacement of one or more of the hydrogen atoms thatwould be available on the unsubstituted group. Suitable substituents areknown in the art and include, but are not limited to, alkyl, alkenyl,alkynyl, alkoxy, alkoxy, aryl, aryloxy, arylthio, aralkyl, heteroaryl,heteroaralkyl, cycloalkyl, heterocyclyl, halo, azido, hydroxyl, thio,alkthiooxy, amino, nitro, nitrile, imino, amido, carboxylic acid,aldehyde, carbonyl, ester, silyl, alkylthio, haloalkoxy (e.g.,perfluoroalkyl such as —CF₃), ═O, ═S, and the like.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example, an alkyl group containing1-6 carbon atoms (C₁₋₆ alkyl) is intended to encompass, C₁, C₂, C₃, C₄,C₅, C₆, C₁₋₆, C₂₋₆, C₃₋₆, C₄₋₆, C₅₋₆, C₁₋₅, C₂₋₅, C₃₋₅, C₄₋₅, C₁₋₄,C₂₋₄, C₃₋₄, C₁₋₃, C₂₋₃, and C₁₋₂ alkyl.

The term “alkyl,” as used herein, refers to saturated, straight- orbranched-chain hydrocarbon radical containing between one and thirtycarbon atoms. In certain embodiments, the alkyl group contains 1-20carbon atoms. Alkyl groups, unless otherwise specified, may optionallybe substituted with one or more substituents. In certain embodiments,the alkyl group contains 1-10 carbon atoms. In certain embodiments, thealkyl group contains 1-6 carbon atoms. In certain embodiments, the alkylgroup contains 1-5 carbon atoms. In certain embodiments, the alkyl groupcontains 1-4 carbon atoms. In certain embodiments, the alkyl groupcontains 1-3 carbon atoms. In certain embodiments, the alkyl groupcontains 1-2 carbon atoms. In certain embodiments, the alkyl groupcontains 1 carbon atom. Representative saturated straight chain alkylsinclude, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl,-n-pentyl, and -n-hexyl; while saturated branched alkyls include, butare not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl,-isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl,4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, and the like. The alkylis attached to the parent molecule by a single bond. Unless statedotherwise in the specification, an alkyl group is optionally substitutedby one or more of substituents which independently include: acyl, alkyl,alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy,amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Perhaloalkyl” refers to an alkyl group in which all of the hydrogenatoms have been replaced with a halogen selected from fluoro, chloro,bromo, and iodo. In some embodiments, all of the hydrogen atoms are eachreplaced with fluoro. In some embodiments, all of the hydrogen atoms areeach replaced with chloro. Examples of perhaloalkyl groups include —CF₃,—CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂, —CF₂Cl and the like.

“Alkyl-cycloalkyl” refers to an -(alkyl)cycloalkyl radical where alkyland cycloalkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for alkyl and cycloalkyl respectively. The“alkyl-cycloalkyl” is bonded to the parent molecular structure throughthe alkyl group. The terms “alkenyl-cycloalkyl” and “alkynyl-cycloalkyl”mirror the above description of “alkyl-cycloalkyl” wherein the term“alkyl” is replaced with “alkenyl” or “alkynyl” respectively, and“alkenyl” or “alkynyl” are as described herein.

“Alkylaryl” refers to an -(alkyl)aryl radical where aryl and alkyl areas disclosed herein and which are optionally substituted by one or moreof the substituents described as suitable substituents for aryl andalkyl respectively. The “alkylaryl” is bonded to the parent molecularstructure through the alkyl group. The terms “-(alkenyl)aryl” and“-(alkynyl)aryl” mirror the above description of “-(alkyl)aryl” whereinthe term “alkyl” is replaced with “alkenyl” or “alkynyl” respectively,and “alkenyl” or “alkynyl” are as described herein.

“Alkyl-heteroaryl” refers to an -(alkyl)heteroaryl radical whereheteroaryl and alkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroaryl and alkyl respectively. The“alkyl-heteroaryl” is bonded to the parent molecular structure throughthe alkyl group. The terms “-(alkenyl)heteroaryl” and“-(alkynyl)heteroaryl” mirror the above description of“-(alkyl)heteroaryl” wherein the term “alkyl” is replaced with “alkenyl”or “alkynyl” respectively, and “alkenyl” or “alkynyl” are as describedherein.

“Alkyl-heterocyclyl” refers to an -(alkyl)heterocycyl radical wherealkyl and heterocyclyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heterocyclyl and alkyl respectively. The“alkyl-heterocyclyl” is bonded to the parent molecular structure throughthe alkyl group. The terms “-(alkenyl)heterocyclyl” and“-(alkynyl)heterocyclyl” mirror the above description of“-(alkyl)heterocyclyl” wherein the term “alkyl” is replaced with“alkenyl” or “alkynyl” respectively, and “alkenyl” or “alkynyl” are asdescribed herein.

The term “alkenyl,” as used herein, denotes a straight- orbranched-chain hydrocarbon radical having at least one carbon-carbondouble bond by the removal of a single hydrogen atom, and containingbetween two and thirty carbon atoms. Alkenyl groups, unless otherwisespecified, may optionally be substituted with one or more substituents.In certain embodiments, the alkenyl group contains 2-20 carbon atoms. Incertain embodiments, the alkenyl group contains 2-10 carbon atoms. Incertain embodiments, the alkenyl group contains 2-6 carbon atoms. Incertain embodiments, the alkenyl group contains 2-5 carbon atoms. Incertain embodiments, the alkenyl group contains 2-4 carbon atoms. Incertain embodiment, the alkenyl group contains 2-3 carbon atoms. Incertain embodiments, the alkenyl group contains 2 carbon atoms. Thealkenyl is attached to the parent molecular structure by a single bond,for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl),but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. The one or morecarbon-carbon double bonds can be internal (such as in 2-butenyl) orterminal (such as in 1-butenyl). Examples of C₂₋₄ alkenyl groups includeethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄),2-butenyl (C₄), butadienyl (C₄) and the like. Examples of C₂₋₆ alkenylgroups include the aforementioned C₂₋₄ alkenyl groups as well aspentenyl (C₅), pentadienyl (C₅), hexenyl (C₆) and the like. Additionalexamples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl(C₈) and the like. Unless stated otherwise in the specification, analkenyl group is optionally substituted by one or more substituentswhich independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy,alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino,imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

The term “alkynyl,” as used herein, denotes a straight- orbranched-chain hydrocarbon radical having at least one carbon-carbontriple bond by the removal of a single hydrogen atom, and containingbetween two and thirty carbon atoms. Alkynyl groups, unless otherwisespecified, may optionally be substituted with one or more substituents.In certain embodiments, the alkynyl group contains 2-20 carbon atoms. Incertain embodiments, the alkynyl group contains 2-10 carbon atoms. Incertain embodiments, the alkynyl group contains 2-6 carbon atoms. Incertain embodiments, the alkynyl group contains 2-5 carbon atoms. Incertain embodiments, the alkynyl group contains 2-4 carbon atoms. Incertain embodiments, the alkynyl group contains 2-3 carbon atoms. Incertain embodiments, the alkynyl group contains 2 carbon atoms. Thealkynyl is attached to the parent molecular structure by a single bond,for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Unless stated otherwise in the specification, an alkynyl group isoptionally substituted by one or more substituents which independentlyinclude: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl,aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

The term “alkoxy” refers to the group —O-alkyl, including from 1 to 30carbon atoms of a straight, branched, cyclic configuration andcombinations thereof, attached to the parent molecular structure throughan oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy,cyclopropyloxy, cyclohexyloxy and the like. “Lower alkoxy” refers toalkoxy groups containing one to six carbons. In some embodiments, C₁-C₄alkoxy is an alkoxy group which encompasses both straight and branchedchain alkyls of from 1 to 4 carbon atoms. Unless stated otherwise in thespecification, an alkoxy group is optionally substituted by one or moresubstituents which independently include: acyl, alkyl, alkenyl, alkynyl,alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido,amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo,haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio,arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate,silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein. The terms“alkenoxy” and “alkynoxy” mirror the above description of “alkoxy”wherein the prefix “alk” is replaced with “alken” or “alkyn”respectively, and the parent “alkenyl” or “alkynyl” terms are asdescribed herein.

The term “alkoxycarbonyl” refers to a group of the formula(alkoxy)(C═O)— attached to the parent molecular structure through thecarbonyl carbon having from 1 to 30 carbon atoms. Thus a C₁-C₆alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atomsattached through its oxygen to a carbonyl linker. The C₁-C₆ designationdoes not include the carbonyl carbon in the atom count. “Loweralkoxycarbonyl” refers to an alkoxycarbonyl group wherein the alkylportion of the alkoxy group is a lower alkyl group. In some embodiments,C₁-C₄ alkoxy is an alkoxy group which encompasses both straight andbranched chain alkoxy groups of from 1 to 4 carbon atoms. Unless statedotherwise in the specification, an alkoxycarbonyl group is optionallysubstituted by one or more substituents which independently include:acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl,aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein. The terms“alkenoxycarbonyl” and “alkynoxycarbonyl” mirror the above descriptionof “alkoxycarbonyl” wherein the prefix “alk” is replaced with “alken” or“alkyn” respectively, and the parent “alkenyl” or “alkynyl” terms are asdescribed herein.

“Acyl” refers to R—C(O)— groups such as, but not limited to,(alkyl)-C(O)—, (alkenyl)-C(O)—, (alkynyl)-C(O)—, (aryl)-C(O)—,(cycloalkyl)-C(O)—, (heteroaryl)-C(O)—, (heteroalkyl)-C(O)—, and(heterocycloalkyl)-C(O)—, wherein the group is attached to the parentmolecular structure through the carbonyl functionality. In someembodiments, it is a C₁-C₁₀ acyl radical which refers to the totalnumber of chain or ring atoms of the, for example, alkyl, alkenyl,alkynyl, aryl, cyclohexyl, heteroaryl or heterocycloalkyl portion plusthe carbonyl carbon of acyl. For example, a C₄-acyl has three other ringor chain atoms plus carbonyl. If the R radical is heteroaryl orheterocycloalkyl, the hetero ring or chain atoms contribute to the totalnumber of chain or ring atoms. Unless stated otherwise in thespecification, the “R” of an acyloxy group can be optionally substitutedby one or more substituents which independently include: acyl, alkyl,alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy,amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or2), or —O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen,alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Acyloxy” refers to a R(C═O)O— radical wherein “R” can be alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl,cyclohexyl, heteroaryl or heterocycloalkyl, which are as describedherein. The acyloxy group is attached to the parent molecular structurethrough the oxygen functionality In some embodiments, an acyloxy groupis a C₁-C₄ acyloxy radical which refers to the total number of chain orring atoms of the alkyl, alkenyl, alkynyl, aryl, cyclohexyl, heteroarylor heterocycloalkyl portion of the acyloxy group plus the carbonylcarbon of acyl, i.e., a C₄-acyloxy has three other ring or chain atomsplus carbonyl. If the R radical is heteroaryl or heterocycloalkyl, thehetero ring or chain atoms contribute to the total number of chain orring atoms. Unless stated otherwise in the specification, the “R” of anacyloxy group is optionally substituted by one or more substituentswhich independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy,alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino,imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl and each of thesemoieties can be optionally substituted as defined herein.

“Amino” or “amine” refers to a —N(R^(b))₂, —N(R^(b))R^(b)—, or—R^(b)N(R^(b))R^(b)— radical group, where each R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon) orheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.When a —N(R^(b))₂ group has two R^(b) other than hydrogen, they can becombined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-memberedring. For example, —N(R^(b))₂ is meant to include, but not be limitedto, 1-pyrrolidinyl and 4-morpholinyl. In some embodiments, the term“amino” refers to the group —NR′₂, wherein each R′ is, independently,hydrogen, a carbon moiety, such as, for example, an alkyl, alkenyl,alkynyl, aryl or heteroaryl group, as defined herein, or two R′ groupstogether with the nitrogen atom to which they are bound form a 5-8membered ring. Unless stated otherwise in the specification, an aminogroup is optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

The terms “amine” and “amino” also refer to N-oxides of the groupsN⁺(H)(R^(a))O⁻, and —N⁺(R^(a))(R^(a))O—, R^(a) as described above, wherethe N-oxide is bonded to the parent molecular structure through the Natom. N-oxides can be prepared by treatment of the corresponding aminogroup with, for example, hydrogen peroxide or m-chloroperoxybenzoicacid. The person skilled in the art is familiar with reaction conditionsfor carrying out the N-oxidation.

“Amide” or “amido” refers to a chemical moiety with formula—C(O)N(R^(b))₂ or —NR^(b)C(O)R^(b), where R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon) orheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.In some embodiments, this radical is a C₁-C₄ amido or amide radical,which includes the amide carbonyl in the total number of carbons in theradical. When a —C(O)N(R^(b))₂ has two R^(b) other than hydrogen, theycan be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, 7- or8-membered ring. For example, the N(R^(b))₂ portion of a —C(O)N(R^(b))₂radical is meant to include, but not be limited to, 1-pyrrolidinyl and4-morpholinyl. In some embodiments, wherein each R′ is, independently,hydrogen or a carbon moiety, such as, for example, an alkyl, alkenyl,alkynyl, aryl or heteroaryl group, as defined herein, or two R′ groupstogether with the nitrogen atom to which they are bound form a 5-8membered ring. Unless stated otherwise in the specification, an amidoR^(b) group is optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)₁R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is 1or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

The term “amide” or “amido” is inclusive of an amino acid or a peptidemolecule. Any amine, hydroxy, or carboxyl side chain on the compoundsdescribed herein can be transformed into an amide group. The proceduresand specific groups to make such amides are known to those of skill inthe art and can readily be found in reference sources such as Greene andWuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley &Sons, New York, N.Y., 1999, which is incorporated herein by reference inits entirety.

“Amidino” refers to both the —C(═NR^(b))N(R^(b))₂ and—N(R^(b))—C(═NR^(b))— radicals, where each R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon) orheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.

“Aromatic” or “aryl” refers to a radical with six to ten ring atoms(e.g., C₆-C₁₀ aromatic or C₆-C₁₀ aryl) which has at least one ringhaving a conjugated pi electron system which is carbocyclic (e.g.,phenyl, fluorenyl, and naphthyl). For example, bivalent radicals formedfrom substituted benzene derivatives and having the free valences atring atoms are named as substituted phenylene radicals. In otherembodiments, bivalent radicals derived from univalent polycyclichydrocarbon radicals whose names end in “-yl” by removal of one hydrogenatom from the carbon atom with the free valence are named by adding“-idene” to the name of the corresponding univalent radical, e.g., anaphthyl group with two points of attachment is termed naphthylidene.Whenever it appears herein, a numerical range such as “6 to 10 aryl”refers to each integer in the given range; e.g., “6 to 10 ring atoms”means that the aryl group can consist of 6 ring atoms, 7 ring atoms,etc., up to and including 10 ring atoms. The term includes monocyclic orfused-ring polycyclic (i.e., rings which share adjacent pairs of ringatoms) groups. In certain embodiments of the present invention, “aryl”refers to an aromatic ring system which includes, but not limited to,phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear oneor more substituents. Also included within the scope of the term “aryl”,as it is used herein, is a group in which an aryl ring is fused to oneor more non-aromatic rings, such as indanyl, phthalimidyl ortetrahydronaphthalyl, and the like, where the point of attachment is onthe aryl ring. Unless stated otherwise in the specification, an arylmoiety can be optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Aralkyl” or “arylalkyl” refers to an (aryl)alkyl-radical where aryl andalkyl are as disclosed herein and which are optionally substituted byone or more of the substituents described as suitable substituents foraryl and alkyl respectively. The “aralkyl/arylalkyl” is bonded to theparent molecular structure through the alkyl group. The terms“aralkenyl/arylalkenyl” and “aralkynyl/arylalkynyl” mirror the abovedescription of “aralkyl/arylalkyl” wherein the “alkyl” is replaced with“alkenyl” or “alkynyl” respectively, and the “alkenyl” or “alkynyl”terms are as described herein.

As used herein, the term “azido” refers to the group —N₃.

“Carbamate” refers to any of the following radicals: —O—(C═O)—N(R^(b))—,—O—(C═O)—N(R^(b))₂, —N(R^(b))—(C═O)—O—, and —N(R^(b))—(C═O)—OR^(b),wherein each R^(b) is independently selected from alkyl, alkenyl,alkynyl, haloalkyl, heteroalkyl (bonded through a chain carbon),cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bondedthrough a ring carbon), heterocycloalkylalkyl, heteroaryl (bondedthrough a ring carbon) or heteroarylalkyl, unless stated otherwise inthe specification, each of which moiety can itself be optionallysubstituted as described herein.

“Carbonate” refers to a —O—(C═O)—O— radical.

“Carbonyl” refers to a —(C═O)— radical. In some embodiments, the term“carbonyl” refers to the group —C(═O)R′, wherein R′ is, independently, acarbon moiety, such as, for example, an alkyl, alkenyl, alkynyl, aryl orheteroaryl group, as defined herein.

“Carboxaldehyde” or “aldehyde” refers to a —(C═O)H radical.

“Carboxyl” refers to a —(C═O)OH radical.

“Cyano” refers to a —CN radical.

“Cycloalkyl” and “carbocyclyl” each refer to a monocyclic or polycyclicradical that contains only carbon and hydrogen, and can be saturated orpartially unsaturated. Partially unsaturated cycloalkyl groups can betermed “cycloalkenyl” if the carbocycle contains at least one doublebond, or “cycloalkynyl” if the carbocycle contains at least one triplebond. The terms “cycloalkyl” and “carbocyclyl” used alone or as part ofa larger moiety, refer to a saturated monocyclic or bicyclic hydrocarbonring system having from 3-15 carbon ring members. Cycloalkyl groups,unless otherwise specified, may optionally be substituted with one ormore substituents. In certain embodiments, cycloalkyl groups contain3-10 carbon ring members. Whenever it appears herein, a numerical rangesuch as “3-10” refers to each integer in the given range; e.g., “3-10carbon atoms” means that the cycloalkyl group can consist of 3 carbonatoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 10carbon atoms. The term “cycloalkyl” also includes bridged andspiro-fused cyclic structures containing no heteroatoms. In certainembodiments, cycloalkyl groups contain 3-9 carbon ring members. Incertain embodiments, cycloalkyl groups contain 3-8 carbon ring members.In certain embodiments, cycloalkyl groups contain 3-7 carbon ringmembers. In certain embodiments, cycloalkyl groups contain 3-6 carbonring members. In certain embodiments, cycloalkyl groups contain 3-5carbon ring members. Cycloalkyl groups include, without limitation,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. The term “cycloalkyl” also includes saturated hydrocarbonring systems that are fused to one or more aryl or heteroaryl rings,such as decahydronaphthyl or tetrahydronaphthyl, where the point ofattachment is on the saturated hydrocarbon ring. Illustrative examplesof cycloalkyl groups include, but are not limited to the followingmoieties: C₃₋₆ carbocyclyl groups include, without limitation,cyclopropyl (C₃), cyclobutyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆) and the like.Examples of C₃₋₈ carbocyclyl groups include the aforementioned C₃₋₆carbocyclyl groups as well as cycloheptyl (C₇), cycloheptadienyl (C₇),cycloheptatrienyl (C₇), cyclooctyl (C₈), bicyclo[2.2.1]heptanyl,bicyclo[2.2.2]octanyl, and the like. Examples of C₃₋₁₀ carbocyclylgroups include the aforementioned C₃₋₈ carbocyclyl groups as well asoctahydro-1H-indenyl, decahydronaphthalenyl, spiro[4.5]decanyl and thelike. Unless stated otherwise in the specification, a cycloalkyl groupis optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfonyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(R^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Cycloalkyl-alkyl” refers to a —(cycloalkyl)alkyl radical wherecycloalkyl and alkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for cycloalkyl and alkyl respectively. The“cycloalkyl-alkyl” is bonded to the parent molecular structure throughthe cycloalkyl group. The terms “cycloalkyl-alkenyl” and“cycloalkyl-alkynyl” mirror the above description of “cycloalkyl-alkyl”wherein the term “alkyl” is replaced with “alkenyl” or “alkynyl”respectively, and “alkenyl” or “alkynyl” are as described herein.

“Cycloalkyl-heterocycloalkyl” refers to a -(cycloalkyl)heterocycylalkylradical where cycloalkyl and heterocycloalkyl are as disclosed hereinand which are optionally substituted by one or more of the substituentsdescribed as suitable substituents for heterocycloalkyl and cycloalkylrespectively. The “cycloalkyl-heterocycloalkyl” is bonded to the parentmolecular structure through the cycloalkyl group.

“Cycloalkyl-heteroaryl” refers to a -(cycloalkyl)heteroaryl radicalwhere cycloalkyl and heteroaryl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroaryl and cycloalkyl respectively. The“cycloalkyl-heteroaryl” is bonded to the parent molecular structurethrough the cycloalkyl group.

As used herein, a “covalent bond” or “direct bond” refers to a singlebond joining two groups.

“Ester” refers to the group —C(═O)OR′ or —OC(═O)R′, where R′ is selectedfrom alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded through achain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl. In someembodiments, each R′ is, independently, a carbon moiety, such as, forexample, an alkyl, alkenyl, alkynyl, aryl or heteroaryl group, asdefined herein. Any amine, hydroxy, or carboxyl side chain on thecompounds described herein can be esterified. The procedures andspecific groups to make such esters are known to those of skill in theart and can readily be found in reference sources such as Greene andWuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley &Sons, New York, N.Y., 1999, which is incorporated herein by reference inits entirety. Unless stated otherwise in the specification, an estergroup can be optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Ether” refers to a —R^(b)—O—R^(b)— radical where each R^(b) isindependently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Halo”, “halide”, or, alternatively, “halogen” means fluoro, chloro,bromo or iodo. The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and“haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures thatare substituted with one or more halo groups or with combinationsthereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” includehaloalkyl and haloalkoxy groups, respectively, in which the halo isfluorine, such as, but not limited to, trifluoromethyl, difluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Eachof the alkyl, alkenyl, alkynyl and alkoxy groups are as defined hereinand can be optionally further substituted as defined herein.

“Heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” include alkyl,alkenyl and alkynyl radicals, respectively, which have one or moreskeletal chain atoms selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Anumerical range can be given, e.g., C₁-C₄ heteroalkyl which refers tothe chain length in total, which in this example is 4 atoms long. Forexample, a —CH₂OCH₂CH₃ radical is referred to as a “C₄” heteroalkyl,which includes the heteroatom center in the atom chain lengthdescription. Connection to the parent molecular structure can be througheither a heteroatom or a carbon in the heteroalkyl chain. For example,an N-containing heteroalkyl moiety refers to a group in which at leastone of the skeletal atoms is a nitrogen atom. One or more heteroatom(s)in the heteroalkyl radical can be optionally oxidized. One or morenitrogen atoms, if present, can also be optionally quaternized. Forexample, heteroalkyl also includes skeletal chains substituted with oneor more nitrogen oxide (—O—) substituents. Exemplary heteroalkyl groupsinclude, without limitation, ethers such as methoxyethanyl(—CH₂CH₂OCH₃), ethoxymethanyl (—CH₂OCH₂CH₃), (methoxymethoxy)ethanyl(—CH₂CH₂OCH₂OCH₃), (methoxymethoxy)methanyl (—CH₂OCH₂OCH₃) and(methoxyethoxy)methanyl (—CH₂OCH₂CH₂OCH₃) and the like; amines such as—CH₂CH₂NHCH₃, —CH₂CH₂N(CH₃)₂, —CH₂NHCH₂CH₃, —CH₂N(CH₂CH₃)(CH₃) and thelike. Heteroalkyl, heteroalkenyl, and heteroalkynyl groups can each beoptionally substituted by one or more substituents which independentlyinclude: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl,aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of thesemoieties can be optionally substituted as defined herein.

“Heteroalkyl-aryl” refers to a -(heteroalkyl)aryl radical whereheteroalkyl and aryl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroalkyl and aryl respectively. The“heteroalkyl-aryl” is bonded to the parent molecular structure throughan atom of the heteroalkyl group.

“Heteroalkyl-heteroaryl” refers to a -(heteroalkyl)heteroaryl radicalwhere heteroalkyl and heteroaryl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroalkyl and heteroaryl respectively. The“heteroalkyl-heteroaryl” is bonded to the parent molecular structurethrough an atom of the heteroalkyl group.

“Heteroalkyl-heterocycloalkyl” refers to a-(heteroalkyl)heterocycloalkyl radical where heteroalkyl andheterocycloalkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroalkyl and heterocycloalkyl respectively. The“heteroalkyl-heterocycloalkyl” is bonded to the parent molecularstructure through an atom of the heteroalkyl group.

“Heteroalkyl-cycloalkyl” refers to a -(heteroalkyl)cycloalkyl radicalwhere heteroalkyl and cycloalkyl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroalkyl and cycloalkyl respectively. The“heteroalkyl-cycloalkyl” is bonded to the parent molecular structurethrough an atom of the heteroalkyl group.

The term “heteroatom” refers to boron, phosphorus, silicon, selenium,nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogenor sulfur, and any quaternized form of a basic nitrogen.

“Heteroaryl” or, alternatively, “heteroaromatic” refers to a refers to aradical of a 5-18 membered monocyclic or polycyclic (e.g., bicyclic ortricyclic) aromatic ring system (e.g., having 6, 10 or 14π electronsshared in a cyclic array) having ring carbon atoms and 1-6 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen, phosphorousand sulfur (“5-18 membered heteroaryl”). Whenever it appears herein, anumerical range such as “5 to 18” refers to each integer in the givenrange; e.g., “5 to 18 ring atoms” means that the heteroaryl group canconsist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ringatoms. For example, bivalent radicals derived from univalent heteroarylradicals whose names end in “-yl” by removal of one hydrogen atom fromthe atom with the free valence are named by adding “-idene” to the nameof the corresponding univalent radical, e.g., a pyridyl group with twopoints of attachment is a pyridylidene. Heteroaryl polycyclic ringsystems can include one or more heteroatoms in one or both rings.

For example, an N-containing “heteroaromatic” or “heteroaryl” moietyrefers to an aromatic group in which at least one of the skeletal atomsof the ring is a nitrogen atom. One or more heteroatom(s) in theheteroaryl radical can be optionally oxidized. One or more nitrogenatoms, if present, can also be optionally quaternized. Heteroaryl alsoincludes ring systems substituted with one or more nitrogen oxide (—O—)substituents, such as pyridinyl N-oxides. The heteroaryl is attached tothe parent molecular structure through any atom of the ring(s).

“Heteroaryl” also includes ring systems wherein the heteroaryl ring, asdefined above, is fused with one or more aryl groups wherein the pointof attachment to the parent molecular structure is either on the aryl oron the heteroaryl ring, or wherein the heteroaryl ring, as definedabove, is fused with one or more cycloalkyl or heterocycyl groupswherein the point of attachment to the parent molecular structure is onthe heteroaryl ring. For polycyclic heteroaryl groups wherein one ringdoes not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl andthe like), the point of attachment to the parent molecular structure canbe on either ring, i.e., either the ring bearing a heteroatom (e.g.,2-indolyl) or the ring that does not contain a heteroatom (e.g.,5-indolyl). In some embodiments, a heteroaryl group is a 5-10 memberedaromatic ring system having ring carbon atoms and 1-4 ring heteroatomsprovided in the aromatic ring system, wherein each heteroatom isindependently selected from nitrogen, oxygen, phosphorous, and sulfur(“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group isa 5-8 membered aromatic ring system having ring carbon atoms and 1-4ring heteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen, phosphorous,and sulfur (“5-8 membered heteroaryl”). In some embodiments, aheteroaryl group is a 5-6 membered aromatic ring system having ringcarbon atoms and 1-4 ring heteroatoms provided in the aromatic ringsystem, wherein each heteroatom is independently selected from nitrogen,oxygen, phosphorous, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, phosphorous, and sulfur. In someembodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatomsselected from nitrogen, oxygen, phosphorous, and sulfur. In someembodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selectedfrom nitrogen, oxygen, phosphorous, and sulfur.

In some embodiments, the terms “heteroaryl” used alone or as part of alarger moiety, e.g., “heteroaralkyl”, refer to an aromatic monocyclic orbicyclic hydrocarbon ring system having 5-10 ring atoms wherein the ringatoms comprise, in addition to carbon atoms, from one to fiveheteroatoms. Heteroaryl groups, unless otherwise specified, mayoptionally be substituted with one or more substituents. When used inreference to a ring atom of a heteroaryl group, the term “nitrogen”includes a substituted nitrogen. Heteroaryl groups include, withoutlimitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. Theterms “heteroaryl” and “heteroar-”, as used herein, also include groupsin which a heteroaryl ring is fused to one or more aryl, cycloalkyl orheterocycloalkyl rings, wherein the point of attachment is on theheteroaryl ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, andtetrahydroisoquinolinyl.

Examples of heteroaryls include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.,thienyl). Unless stated otherwise in the specification, a heteroarylmoiety is optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃—, —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl and each of thesemoieties can be optionally substituted as defined herein.

The term “heteroaralkyl” refers to an alkyl group, as defined herein,substituted by a heteroaryl group, as defined herein, wherein the pointof attachment is on the alkyl group.

“Heteroaryl-heterocycloalkyl” refers to an -(heteroaryl)heterocycloalkylradical where heteroaryl and heterocycloalkyl are as disclosed hereinand which are optionally substituted by one or more of the substituentsdescribed as suitable substituents for heteroaryl and heterocycloalkylrespectively. The “heteroaryl-heterocycloalkyl” is bonded to the parentmolecular structure through an atom of the heteroaryl group.

“Heteroaryl-cycloalkyl” refers to an -(heteroaryl)cycloalkyl radicalwhere heteroaryl and cycloalkyl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroaryl and cycloalkyl respectively. The“heteroaryl-cycloalkyl” is bonded to the parent molecular structurethrough a carbon atom of the heteroaryl group.

As used herein, the terms “heterocycloalkyl”, “heterocyclyl” or“heterocarbocyclyl” refer to any 3- to 18-membered non-aromatic radicalmonocyclic or polycyclic moiety comprising at least one heteroatomselected from nitrogen, oxygen, phosphorous and sulfur. A heterocyclylgroup can be a monocyclic, bicyclic, tricyclic or tetracyclic ringsystem, wherein the polycyclic ring systems can be a fused, bridged orspiro ring system. Heterocyclyl polycyclic ring systems can include oneor more heteroatoms in one or both rings. A heterocyclyl group can besaturated or partially unsaturated. Partially unsaturatedheterocycloalkyl groups can be termed “heterocycloalkenyl” if theheterocyclyl contains at least one double bond, or “heterocycloalkynyl”if the heterocyclyl contains at least one triple bond. Whenever itappears herein, a numerical range such as “5 to 18” refers to eachinteger in the given range; e.g., “5 to 18 ring atoms” means that theheterocyclyl group can consist of 5 ring atoms, 6 ring atoms, etc., upto and including 18 ring atoms. For example, bivalent radicals derivedfrom univalent heterocyclyl radicals whose names end in “-yl” by removalof one hydrogen atom from the atom with the free valence are named byadding “-idene” to the name of the corresponding univalent radical,e.g., a piperidine group with two points of attachment is apiperidylidene.

In some embodiments, these terms refer to a stable non-aromatic 5-7membered monocyclic hydrocarbon or stable non-aromatic 7-10 memberedbicyclic hydrocarbon that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more heteroatoms.Heterocycloalkyl or heterocyclyl groups, unless otherwise specified, mayoptionally be substituted with one or more substituents. When used inreference to a ring atom of a heterocycloalkyl group, the term“nitrogen” includes a substituted nitrogen. The heteroatom(s) in theheterocyclyl radical can be optionally oxidized. One or more nitrogenatoms, if present, can be optionally quaternized. Heterocyclyl alsoincludes ring systems substituted with one or more nitrogen oxide (—O—)substituents, such as piperidinyl N-oxides. The heterocyclyl is attachedto the parent molecular structure through any atom of any of thering(s). The point of attachment of a heterocycloalkyl group may be atany of its heteroatom or carbon ring atoms that results in a stablestructure.

In some embodiments, a heterocyclyl group is a 3-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, phosphorous and sulfur (“3-10 membered heterocyclyl”).In some embodiments, a heterocyclyl group is a 5-8 membered non-aromaticring system having ring carbon atoms and 1-4 ring heteroatoms, whereineach heteroatom is independently selected from nitrogen, oxygen,phosphorous and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, phosphorousand sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen,oxygen phosphorous and sulfur. In some embodiments, the 5-6 memberedheterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen,phosphorous and sulfur. In some embodiments, the 5-6 memberedheterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen,phosphorous and sulfur.

Examples of heterocycloalkyl groups include, without limitation,tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.“Heterocycloalkyl” also include groups in which the heterocycloalkylring is fused to one or more aryl, heteroaryl or cycloalkyl rings, suchas indolinyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, wherethe radical or point of attachment is on the heterocycloalkyl ring.

Exemplary 3-membered heterocyclyls containing 1 heteroatom include,without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-memberedheterocyclyls containing 1 heteroatom include, without limitation,azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclylscontaining 1 heteroatom include, without limitation, tetrahydrofuranyl,dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl,dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-memberedheterocyclyls containing 2 heteroatoms include, without limitation,dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-memberedheterocyclyls containing 3 heteroatoms include, without limitation,triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-memberedheterocyclyl groups containing 1 heteroatom include, without limitation,piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary6-membered heterocyclyl groups containing 2 heteroatoms include, withoutlimitation, piperazinyl, morpholinyl, dithianyl, dioxanyl, andtriazinanyl. Exemplary 7-membered heterocyclyl groups containing 1heteroatom include, without limitation, azepanyl, oxepanyl andthiepanyl. Exemplary 8-membered heterocyclyl groups containing 1heteroatom include, without limitation, azocanyl, oxecanyl andthiocanyl. Exemplary bicyclic heterocyclyl groups include, withoutlimitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl,tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl,octahydroisochromenyl, decahydronaphthyridinyl,decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,phthalimidyl, naphthalimidyl, chromanyl, chromenyl,1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

Unless stated otherwise, heterocyclyl moieties are optionallysubstituted by one or more substituents which independently include:acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl,aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃—, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))_(C)(O)_(N)(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), or —O—P(═O)(OR^(a))₂where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl and each of thesemoieties can be optionally substituted as defined herein.

“Heterocyclyl-alkyl” refers to a -(heterocyclyl)alkyl radical whereheterocyclyl and alkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heterocyclyl and alkyl respectively. The“heterocyclyl-alkyl” is bonded to the parent molecular structure throughany atom of the heterocyclyl group. The terms “heterocyclyl-alkenyl” and“heterocyclyl-alkynyl” mirror the above description of“heterocyclyl-alkyl” wherein the term “alkyl” is replaced with “alkenyl”or “alkynyl” respectively, and “alkenyl” or “alkynyl” are as describedherein.

As used herein, the term “hydroxyl” or “hydroxy” refers to the group—OH.

As used herein, the term “imide” or “imido” refers to the group—C(═NR′)N(R′)₂ or —NR′C(═NR′)R′ wherein each R′ is, independently,hydrogen or a carbon moiety, such as, for example, an alkyl, alkenyl,alkynyl, aryl or heteroaryl group, as defined herein, or wherein two R′groups together with the nitrogen atom to which they are bound form a5-8 membered ring.

“Imino” refers to the “—(C═N)—R^(b)” radical where R^(b) is selectedfrom hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein.

“Moiety” refers to a specific segment or functional group of a molecule.Chemical moieties are often recognized chemical entities embedded in orappended to a molecule.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Phosphate” refers to a —O—P(═O)(OR^(b))₂ radical, where each R^(b) isindependently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(a) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

“Phosphonate” refers to a —O—P(═O)(R^(b))(OR^(b)) radical, where eachR^(b) is independently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(a) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

“Phosphinate” refers to a —P(═O)(R^(b))(OR^(b)) radical, where eachR^(b) is independently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(a) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

“Silyl” refers to a —Si(R^(b))₃ radical where each R^(b) isindependently selected from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, R^(b) is a carbon moiety, suchas, for example, an alkyl, alkenyl, alkynyl, aryl or heteroaryl group.

“Sulfanyl”, “sulfide”, and “thio” each refer to the radical —S—R^(b),wherein R^(b) is selected from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. For instance, an “alkylthio” refers to the“alkyl-S-” radical, and “arylthio” refers to the “aryl-S-” radical, eachof which are bound to the parent molecular group through the S atom. Theterms “sulfide”, “thiol”, “mercapto”, and “mercaptan” can also eachrefer to the group —R^(b)SH. As used herein, the term “alkthiooxy”refers to the group —SR′, wherein each R′ is, independently, a carbonmoiety, such as, for example, an alkyl, alkenyl, or alkynyl group, asdefined herein. As used herein, the term “arylthio” refers to the group—SR′, wherein each R′ is an aryl or heteroaryl group, as defined herein.

“Sulfinyl” or “sulfoxide” refers to the —S(O)—R^(b) radical, wherein for“sulfinyl”, R^(b) is H and for “sulfoxide”, R^(b) is selected fromalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded through a chaincarbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl(bonded through a ring carbon), heterocycloalkylalkyl, heteroaryl(bonded through a ring carbon) or heteroarylalkyl, unless statedotherwise in the specification, each of which moiety can itself beoptionally substituted as described herein.

“Sulfonyl” or “sulfone” refers to the —S(O₂)—R^(b) radical, whereinR^(b) is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Sulfonamidyl” or “sulfonamido” refers to the following radicals:—S(═O)₂—N(R^(b))₂, —N(R^(b))—S(═O)₂—R^(b), —S(═O)₂—N(R^(b))—, or—N(R^(b))—S(═O)₂—, where each R^(b) is independently selected fromhydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein. The R^(b) groups in—S(═O)₂—N(R^(b))₂ can be taken together with the nitrogen to which theyare attached to form a 4-, 5-, 6-, or 7-membered heterocyclyl ring. Insome embodiments, the term designates a C₁-C₄ sulfonamido, wherein eachR^(b) in the sulfonamido contains 1 carbon, 2 carbons, 3 carbons, or 4carbons total.

“Sulfoxyl” or “sulfoxide” refers to a —S(═O)2OH radical.

“Sulfonate” refers to a —S(═O)₂—OR^(b) radical, wherein R^(b) isselected from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein.

“Thiocarbonyl” refers to a —(C═S)— radical.

“Urea” refers to a —N(R^(b))—(C═O)—N(R^(b))₂ or—N(R^(b))—(C═O)—N(R^(b))— radical, where each R^(b) is independentlyselected from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein.

“Silyl” refers to a —Si(R^(b))₃ radical where each R^(b) isindependently selected from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Sulfanyl”, “sulfide”, and “thio” each refer to the radical —S—R^(b),wherein R^(b) is selected from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. For instance, an “alkylthio” refers to the“alkyl-S-” radical, and “arylthio” refers to the “aryl-S-” radical, eachof which are bound to the parent molecular group through the S atom. Theterms “sulfide”, “thiol”, “mercapto”, and “mercaptan” can also eachrefer to the group —R^(b)SH.

“Sulfinyl” or “sulfoxide” refers to the —S(O)—R^(b) radical, wherein for“sulfinyl”, R^(b) is H and for “sulfoxide”, R^(b) is selected fromalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded through a chaincarbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl(bonded through a ring carbon), heterocycloalkylalkyl, heteroaryl(bonded through a ring carbon) or heteroarylalkyl, unless statedotherwise in the specification, each of which moiety can itself beoptionally substituted as described herein.

“Sulfonyl” or “sulfone” refers to the —S(O₂)—R^(b) radical, whereinR^(b) is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Sulfonamidyl” or “sulfonamido” refers to the following radicals:—S(═O)₂—N(R^(b))₂, —N(R^(b))—S(═O)₂—R^(b), —S(═O)₂—N(R^(b))—, or—N(R^(b))—S(═O)₂—, where each R^(b) is independently selected fromhydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein. The R^(b) groups in—S(═O)₂—N(R^(b))₂ can be taken together with the nitrogen to which theyare attached to form a 4-, 5-, 6-, or 7-membered heterocyclyl ring. Insome embodiments, the term designates a C₁-C₄ sulfonamido, wherein eachR^(b) in the sulfonamido contains 1 carbon, 2 carbons, 3 carbons, or 4carbons total.

“Sulfoxyl” or “sulfoxide” refers to a —S(═O)₂OH radical.

“Sulfonate” refers to a —S(═O)₂—OR^(b) radical, wherein R^(b) isselected from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein.

“Thiocarbonyl” refers to a —(C═S)— radical.

“Urea” refers to a —N(R^(b))—(C═O)—N(R^(b))₂ or—N(R^(b))—(C═O)—N(R^(b))— radical, where each R^(b) is independentlyselected from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

A “leaving group or atom” is any group or atom that will, under thereaction conditions, cleave from the starting material, thus promotingreaction at a specified site. Suitable non-limiting examples of suchgroups unless otherwise specified include halogen atoms, mesyloxy,p-nitrobenzensulphonyloxy, trifluoromethyloxy, and tosyloxy groups.

“Protecting group” has the meaning conventionally associated with it inorganic synthesis, i.e., a group that selectively blocks one or morereactive sites in a multifunctional compound such that a chemicalreaction can be carried out selectively on another unprotected reactivesite and such that the group can readily be removed after the selectivereaction is complete. A variety of protecting groups are disclosed, forexample, in T. H. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, Third Edition, John Wiley & Sons, New York (1999),incorporated herein by reference in its entirety. For example, a hydroxyprotected form is where at least one of the hydroxy groups present in acompound is protected with a hydroxy protecting group. Likewise, aminesand other reactive groups can similarly be protected.

The term “unsaturated”, as used herein, means that a moiety has one ormore double or triple bonds.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aromatic groups, such asaryl or heteroaryl moieties, as defined herein.

The teen “diradical” as used herein refers to an alkyl, alkenyl,alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, andheteroaralkyl groups, as described herein, wherein 2 hydrogen atoms areremoved to form a divalent moiety. Diradicals are typically end with asuffix of “-ene”. For example, alkyl diradicals are referred to asalkylenes (for example:

and —(CR′₂)_(x)— wherein R′ is hydrogen or other substituent and x is 1,2, 3, 4, 5 or 6); alkenyl diradicals are referred to as “alkenylenes”;alkynyl diradicals are referred to as “alkynylenes”; aryl and aralkyldiradicals are referred to as “arylenes” and “aralkylenes”, respectively(for example:

heteroaryl and heteroaralkyl diradicals are referred to as“heteroarylenes” and “heteroaralkylenes”, respectively (for example:

cycloalkyl diradicals are referred to as “cycloalkylenes”;heterocycloalkyl diradicals are referred to as “heterocycloalkylenes”;and the like.

As used herein, the terms “substituted” or “substitution” mean that atleast one hydrogen present on a group atom (e.g., a carbon or nitrogenatom) is replaced with a permissible substituent, e.g., a substituentwhich upon substitution for the hydrogen results in a stable compound,e.g., a compound which does not spontaneously undergo transformationsuch as by rearrangement, cyclization, elimination, or other reaction.Unless otherwise indicated, a “substituted” group can have a substituentat one or more substitutable positions of the group, and when more thanone position in any given structure is substituted, the substituent iseither the same or different at each position. Substituents include oneor more group(s) individually and independently selected from acyl,alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl,aryloxy, amino, amido, azide, carbonate, carbonyl, heteroalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo,haloalkoxy, haloalkyl, ester, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)R^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), —O—P(═O)(OR^(a))₂,where each R^(a) is independently hydrogen, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl and each of thesemoieties can be optionally substituted as defined herein. For example, acycloalkyl substituent can have a halide substituted at one or more ringcarbons, and the like. The protecting groups that can form theprotective derivatives of the above substituents are known to those ofskill in the art and can be found in references such as Greene and Wuts,above.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.In case of conflict, the present application, including any definitionsherein, will control.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the chemical synthesis of IPI-926 (V-a) from cis-decalonestarting material (I-a) as described in Tremblay et al., “Discovery of aPotent and Orally Active Hedgehog Pathway Antagonist (IPI-926)” J. Med.Chem. (2009) 52:4400-4418. Step 1 of the depicted synthesis, theK-selectride reduction, provided the reduced product (S)-(II-a)in >96:4β to α selectivity.

FIG. 2 depicts the ruthenium-catalyzed transfer-hydrogenation of (I-a).Transfer-hydrogenation of (I-a) using 1 mol % of the achiral rutheniumtransfer-hydrogenation catalyst (iii-g) provided the reduced product(S)-(II-a) in >98.7:1.3 β:α selectivity.

DETAILED DESCRIPTION

For example, in one aspect, provided herein is a process for preparing acompound of formula (II):

or its pharmaceutically acceptable forms thereof;

from a compound of formula (I):

or its pharmaceutically acceptable forms thereof;

wherein:

R¹ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —OR¹⁶, —C(O)R¹⁶, —CO₂R¹⁶,—SO₂R¹⁶, —C(O)N(R¹⁷)(R¹⁷), —[C(R¹⁶)₂]_(q)—R¹⁶, —[(W)—N(R¹⁷)C(O)]_(q)R¹⁶,—[(W)—C(O)]_(q)R¹⁶, —[(W)—C(O)O]_(q)R¹⁶, —[(W)—SO₂]_(q)R¹⁶,—[(W)—N(R¹⁷)SO₂]_(q)R¹⁶, —[(W)—C(O)N(R¹⁷)]_(q)R¹⁷, —[(W)—O]_(q)R¹⁶,—[(W)—N(R¹⁷)]_(q)R¹⁶, or —[(W)—S]_(q)R¹⁶; wherein W is a diradical and qis 1, 2, 3, 4, 5, or 6;

each R² and R³ is, independently, H, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl,haloalkyl, halo, —OR¹⁶, —OR¹⁶, —N(R¹⁷)₂, or —SR¹⁶, or R² and R³ takentogether form a double bond or form a group:

wherein Z is NR¹⁷, O, or C(R¹⁸)₂;

R⁴ is independently H, halo, —OR¹⁶, —N(R¹⁷)₂, or —SR¹⁶;

each R⁵ and R⁶, is, independently, H, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halo,—OR¹⁶, —N(R¹⁷)₇, or —SR¹⁶; or R⁵ and R⁶ taken together with the carbonto which they are bonded form C═O, C═S, C═N—OR¹⁷, C═N—R¹⁷, C═N—N(R¹⁷)₂,or form an optionally substituted 3-8 membered ring;

each R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ is, independently, H, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl,heteroaryl, heteroaralkyl, halo, —OR¹⁶, —N(R¹⁷)₂, or —SR¹⁶;

or R¹¹ and R¹² taken together, form a double bond;

or R¹⁰ and R¹¹ taken together, or R¹¹ and R¹² taken together, form agroup:

wherein Z is NR¹⁷, O, or C(R¹⁸)₂;

each R¹⁴ and R¹⁵ is, independently, H, halo, —OR¹⁶, —N(R¹⁷)₂, or —SR¹⁶;or R¹⁴ and R¹⁵ taken together with the carbon to which they are bondedform C═O or C═S;

X is a bond or the group —C(R¹⁹)₂—, wherein each R¹⁹ is, independently,H, alkyl, aralkyl, halo, —CN, —OR¹⁶, or —N(R¹⁷)₂;

R¹⁶ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, heteroaralkyl or —[C(R²⁰)₂]_(p)—R²¹ wherein p is0-6; or any two occurrences of R¹⁶ on the same substituent are takentogether to form a 4-8 membered optionally substituted ring;

R¹⁷ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, heteroaralkyl, —C(═O)R²⁰, —C(═O)OR²⁰, —SO₂R²⁰,—C(═O)N(R²⁰)₂, or —[C(R²⁰)₂]_(p)—R²¹ wherein p is 0-6; or any twooccurrences of R¹⁷ on the same substituent are taken together to form a4-8 membered optionally substituted ring;

R¹⁸ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, heteroaralkyl, halo, —CN, —OR²⁰,—OSi(R²⁰)₃,—C(═O)R²⁰, —C(═O)OR²⁰, —SO₂R²⁰ or —C(═O)N(R²⁰)₂;

R²⁰ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, or heteroaralkyl; or any two occurrences of R²⁰ onthe same substituent are taken together to form a 4-8 memberedoptionally substituted ring;

R²¹ is —OR²², —N(R²²)C(═O)R²², —N(R²²)C(═O)OR²², —N(R²²)SO₂(R²²),—C(═O)R²²N(R²²)₂, —OC(═O)R²²N(R²²)(R²²), —SO₂N(R²²)(R²²), —N(R²²)(R²²),—C(═O)OR²², —C(═O)N(OH)(R²²), —OS(O)₂OR²², —S(O)₂OR²²,—OP(═O)(OR²²)(OR²²), —N(R²²)P(O)(OR²²)(OR²²), or —P(═O)(OR²²)(OR²²); and

R²² is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, heteroaralkyl; or any two occurrences of R²² on thesame substituent are taken together to form a 4-8 membered optionallysubstituted ring;

the process comprising reacting a compound of formula (I) or itspharmaceutically acceptable forms thereof with a transfer-hydrogenationcatalyst in order to provide a compound of formula (II) or itspharmaceutically acceptable forms thereof.

For example, in one aspect, provided herein is a process for preparing acompound of formula (II):

or its pharmaceutically acceptable forms thereof;from a compound of formula (I):

or its pharmaceutically acceptable forms thereof;wherein:

R¹ is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, heteroaralkyl, haloalkyl, heteroalkyl, —C(O)R¹⁶,—CO₂R¹⁶, —SO₂R¹⁶, —C(O)N(R¹⁷)(R¹⁷), —[C(R²³)₂]_(q)—R²³,—[(W)—N(R¹⁷)C(O)]_(q)R¹⁶, —[(W)—C(O)N(R¹⁷)]_(q)R¹⁷,—[(W)—N(R¹⁷)]_(q)R¹⁶, or —[(W)—S]_(q)R¹⁶; wherein W is (CH₂)_(q) andeach q is independently 1, 2, 3, 4, 5, or 6;

each R² and R³ is, independently, H, alkyl, alkenyl, alkynyl, aralkyl,heteroaralkyl, haloalkyl, heteroalkyl, CN, NO₂, halo, —OR¹⁶, —N(R¹⁷)₂,or —SR¹⁶, or R² and R³ taken together form a double bond or form agroup:

wherein Z is NR¹⁷, O, or C(R¹⁸)₂;

R⁴ is H, halo, —OR¹⁶, —N(R¹⁷)₂, or —SR¹⁶;

each R⁵ and R⁶, is, independently, H, alkyl, alkenyl, alkynyl, aralkyl,heteroaralkyl, heteroalkyl; or R⁵ and R⁶ taken together with the carbonto which they are bonded form C═O or C═S;

each R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ is, independently, H, alkyl,alkenyl, alkynyl, aralkyl, heteroaralkyl, heteroalkyl, halo, or —OR¹⁶,or R¹¹ and R¹² taken together, form a double bond;

each R¹⁴ and R¹⁵ is, independently, H, alkyl, alkenyl, alkynyl, aralkyl,heteroaralkyl, heteroalkyl, halo, —OR¹⁶, —N(R¹⁷)₂, or —SR¹⁶; or R¹⁴ andR¹⁵ taken together with the carbon to which they are bonded form C═O orC═S;

X is a bond or the group —C(R¹⁹)₂—, wherein each R¹⁹ is, independently,H, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, heteroalkyl, halo,—CN, —NO₂, —OR¹⁶, or —N(R¹⁷)₂;

R¹⁶ is alkyl, alkenyl, alkynyl, alkoxy, arylalkoxy, aryl, cycloalkyl,heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or any twooccurrences of R¹⁶ on the same substituent are taken together to form a4-8 membered optionally substituted ring;

R¹⁷ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, heteroaralkyl, —C(═O)R²⁰, —C(═O)OR²⁰, —SO₂R²⁰, or—C(═O)N(R²⁰)₂; or any two occurrences of R¹⁷ on the same substituent aretaken together to form a 4-8 membered optionally substituted ring;

R¹⁸ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, heteroaralkyl, heteroalkyl, halo, —CN, —OR²⁰,—OSi(R²⁰)₃, —N(R¹⁷)₂, —C(═O)R²⁰, —C(═O)OR²⁰, —SO₂R²⁰ or —C(═O)N(R²⁰)₂;

R²⁰ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, or heteroaralkyl; or any two occurrences of R²⁰ onthe same substituent are taken together to form a 4-8 memberedoptionally substituted ring; and

R²³ is H, alkyl, alkenyl, alkynyl, amido, or amino;

the process comprising reacting a compound of formula (I) or itspharmaceutically acceptable forms thereof with a transfer-hydrogenationcatalyst in order to provide a compound of formula (II) or itspharmaceutically acceptable forms thereof.

For example, in one aspect, provided herein is a process for preparing acompound of formula (II):

or its pharmaceutically acceptable forms thereof;

from a compound of formula (I):

or its pharmaceutically acceptable forms thereof;

wherein:

R¹ is alkyl, alkenyl, alkynyl, aralkyl, —C(O)R¹⁶,—CO₂R¹⁶, —SO₂R¹⁶,—[C(R²³)₂]_(q)—R²³, —[(W)—N(R¹⁷)C(O)]_(q)R¹⁶, —[(W)—C(O)N(R¹⁷)]_(q)R¹⁷,or —[(W)—N(R¹⁷)]_(q)R, W is (CH₂)_(q) and each q is independently 1, 2,3, 4, 5, or 6;

R⁵ and R⁶ are each H, or R⁵ and R⁶ taken together with the carbon towhich they are bonded form C═O;

R¹¹ and R¹² are each H, or R¹¹ and R¹² taken together form a doublebond;

X is a bond or the group —CH₂—;

R¹⁶ is alkyl, alkenyl, alkynyl, aralkyl, alkoxy, arylalkoxy, orheteroaralkyl;

R¹⁷ is H, alkyl, alkenyl, or alkynyl; and

R²³ is H, alkyl, alkenyl, alkynyl, amido, or amino;

the process comprising reacting a compound of formula (I) or itspharmaceutically acceptable forms thereof with a transfer-hydrogenationcatalyst in order to provide a compound of formula (II) or itspharmaceutically acceptable forms thereof.

In certain embodiments, R¹ is H, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl,haloalkyl, —C(O)R¹⁶, —CO₂R¹⁶, —SO₂R¹⁶, —C(O)N(R¹⁷)(R¹⁷), or—[C(R¹⁶)₂]_(q)—R¹⁶. In certain embodiments, R¹ is H, aralkyl, —C(O)R¹⁶,—CO₂R¹⁶, —SO₂R¹⁶ or —C(O)N(R¹⁷)(R¹⁷). In certain embodiments, R¹ is H,aralkyl or —CO₂R¹⁶.

In certain embodiments, R¹ is H.

In certain embodiments, R¹ is aralkyl (e.g., benzyl).

In certain embodiments, R¹ is —CO₂R¹⁶. In certain embodiments, R¹ is—CO₂R¹⁶ and R¹⁶ is alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycloalkyl, aralkyl, heteroaryl or heteroaralkyl. In certainembodiments, R¹ is a -Boc group (e.g., wherein R¹ is —CO₂R¹⁶ and R¹⁶ ist-butyl). In certain embodiments, R¹ is a -Cbz group (e.g., wherein R¹is —CO₂R¹⁶ and R¹⁶ is benzyl).

In certain embodiments, R² and R³ are taken together form a double bond.

In certain embodiments, R² and R³ form a group:

wherein Z is —NR¹⁷—, —O—, or —C(R¹⁸)₂—. In certain embodiments, Z is—C(R¹⁸)₂—. In certain embodiments, Z is —CH₂—.

In certain embodiments, X is a bond. For example, in certainembodiments, wherein R² and R³ are taken together form a double bond, orwherein R² and R³ form a group:

and Z is —NR¹⁷—, —O—, or —C(R¹⁸)₂—, then X is a bond.

In certain embodiments, X is the group —C(R¹⁹)₂—. In certainembodiments, R¹⁹ is H, e.g., wherein X is —CH₂—.

In certain embodiments, wherein R² and R³ are taken together form adouble bond, then X is the group —C(R¹⁹)₂—. In certain embodiments,wherein R² and R³ are taken together form a double bond, then X is thegroup —CH₂—.

In certain embodiments, R⁴ is H.

In certain embodiments, each R⁵ and R⁶, is, independently, H, or R⁵ andR⁶ taken together, along with the carbon to which they are bonded, formC═O. In certain embodiments, each of R⁵ and R⁶ is independently H. Incertain embodiments, R⁵ and R⁶ taken together with the carbon to whichthey are bonded form C═O.

In certain embodiments, R⁷ and R⁸ are each H.

In certain embodiments, R⁹ and R¹⁰ are each H.

In certain embodiments, R¹¹ is a H.

In certain embodiments, R¹² and R¹³ are each H.

In certain embodiments, R¹⁴ and R¹⁵ are each H.

In certain embodiments, each of R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ andR¹⁵ is H.

In certain embodiments, R¹³ is H, and R¹¹ and R¹² taken together form adouble bond.

In certain embodiments, the compound of formula (I) is a compound of theformula (I-AA):

or its pharmaceutically acceptable forms thereof,

and the compound of formula (II) is a compound of the formula (II-AA):

or its pharmaceutically acceptable forms thereof,

wherein R¹, R², R³, R⁵, R⁶, R¹⁰, R¹¹, R¹², and X are as defined herein.

In certain embodiments, the compound of formula (I) is a compound of theformula (I-AA):

or its pharmaceutically acceptable forms thereof,

and the compound of formula (II) is a compound of the formula (II-AA):

or its pharmaceutically acceptable forms thereof,

wherein X is —(CH₂)—;

R¹ is benzyl, or —CO₂R¹⁶ and R¹⁶ is benzyl;

R² and R³ are taken together to form a double bond;

R⁵ and R⁶ are each hydrogen or R⁵ and R⁶ taken together with the carbonto which they are bonded form C═O; and

R¹⁰, R¹¹ and R¹² are each hydrogen, or R¹¹ and R¹² taken together, forma double bond.

In certain embodiments, the compound of formula (I) is a compound of theformula (I-BB):

or its pharmaceutically acceptable forms thereof,

and the compound of formula (II) is a compound of the formula (II-BB):

or its pharmaceutically acceptable forms thereof,

wherein R¹, R², R³, R⁵, R⁶ and X are as defined herein.

In certain embodiments, the compound of formula (I) is a compound of theformula (I-CC):

or its pharmaceutically acceptable forms thereof,

and the compound of formula (II) is a compound of the formula (II-CC):

or its pharmaceutically acceptable forms thereof,

wherein R¹ and X are as defined herein.

Exemplary compounds of formula (I), and subgenera thereof, are providedin U.S. Pat. No. 7,812,164 and U.S. Publication No. 20090012109, each ofwhich is incorporated herein by reference in their entirety.

In some embodiments, the compound of formula (I) or its pharmaceuticallyacceptable forms thereof include, but are not limited to the following:

or its pharmaceutically acceptable forms thereof.

Suitable compounds of Formula (I) for use in the processes disclosedherein can be accessed from members of the Liliaceae natural productfamily through synthetic methods within the knowledge scope of theskilled artisan. (See., e.g., Li, H.-J. et al., “Chemistry, bioactivityand geographical diversity of steroidal alkaloids from the Liliaceaefamily” Nat. Prod. Rep. (2006) 23:735-752, incorporated herein byreference in its entirety). Compounds of Formula (I) can result from theappropriate transformation of the following non-limiting examples ofknown Veratrum-type natural products, including jervine, jervinone,O-acetyljervine, methyljervine-N-3′-propanoate,1-hydroxy-5,6-dihydrojervine, pseudojervine, verdine, verapatuline,cycloposine, hupehenisine, songbeisine, kuroyurinidine,23-isokuroyurinidine, yibeissine, tortifolisine, peimicine, andebeiensine.

In certain embodiments, the compound of formula (I) or itspharmaceutically acceptable forms thereof, and a compound of formula(II) or its pharmaceutically acceptable forms thereof, are selected fromthe set of compounds, or their pharmaceutically acceptable formsthereof, provided in Tables 1, 2, and 3, and wherein R¹ is as definedabove and herein:

TABLE 1 Compound of formula (I) Compound of formula (II)

(I-a)

(II-a)

(I-b)

(II-b)

(I-c)

(II-c)

(I-d)

(II-d)

TABLE 2 Compound of formula (I) Compound of formula (II)

(I-e)

(II-e)

(I-f)

(II-f)

(I-g)

(II-g)

(I-h)

(II-h)

TABLE 3 Compound of formula (I) Compound of formula (II)

(I-i)

(II-i)

(I-j)

(II-j)

(I-k)

(II-k)

(I-l)

(II-l)

In certain embodiments, R¹ is H.

In certain embodiments, R¹ is aralkyl (e.g., benzyl).

In certain embodiments, R¹ is —CO₂R¹⁶. In certain embodiments, R¹ is—CO₂R¹⁶ and R¹⁶ is alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycloalkyl, aralkyl, heteroaryl or heteroaralkyl. In certainembodiments, R¹ is a -Boc group (e.g., wherein R¹ is —CO₂R¹⁶ and R¹⁶ ist-butyl). In certain embodiments, R¹ is a -Cbz group (e.g., wherein R¹is —CO₂R¹⁶ and R¹⁶ is benzyl).

As used herein, the term “preferentially generates” refers to theproduction of one stereoisomer of a compound of formula (II) in excessover the other stereoisomer. In certain embodiments, the processpreferentially generates a compound of formula (II), or itspharmaceutically acceptable forms thereof, wherein the carbon atom thatis directly attached to the newly-formed hydroxyl group has the (R) or(S) configuration, in greater than 40% diastereomeric excess (de),greater than 50% de, greater than 60% de, greater than 70% de, greaterthan 75% de, greater than 80% de, greater than 85% de, greater than 90%de, greater than 95% de, greater than 98% de, or greater than 99% de, asdetermined by HPLC or other analytical methods known to the skilledartisan.

In certain embodiments, the process preferentially generates a compoundof formula (II), or its pharmaceutically acceptable forms thereof, froma compound of formula (I), or its pharmaceutically acceptable formsthereof, wherein the carbon atom that is directly attached to thenewly-formed hydroxyl group provided in formula (II) has the (R) or (S)configuration.

For example, in certain embodiments, the process preferentiallygenerates a compound of formula (II), or its pharmaceutically acceptableforms thereof, from a compound of formula (I), or its pharmaceuticallyacceptable forms thereof, wherein the newly-formed hydroxyl group hasthe α (alpha) orientation; or the carbon atom that is directly attachedto the newly-formed hydroxyl group has the (R) configuration; or thenewly-formed hydroxyl group has the α (alpha) orientation, and thecarbon atom that is directly attached to the newly-formed hydroxyl grouphas the (R) configuration; e.g., a compound of the formula (R)-(II):

or its pharmaceutically acceptable forms thereof,

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵and X are as defined herein.

In certain embodiments, the process preferentially generates a compoundof formula (II), or its pharmaceutically acceptable forms thereof, froma compound of formula (I), or its pharmaceutically acceptable formsthereof, wherein the newly-formed hydroxyl group has the β (beta)orientation; or the carbon atom that is directly attached to thenewly-formed hydroxyl group has the (S) configuration; or thenewly-formed hydroxyl group has the β (beta) orientation, and the carbonatom that is directly attached to the newly-formed hydroxyl group hasthe (S) configuration; e.g., a compound of the formula (S)-(II):

or its pharmaceutically acceptable forms thereof,

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵and X are as defined herein.

In one embodiment, the process preferentially generates a compound offormula (II), or its pharmaceutically acceptable forms thereof, whereinthe carbon atom that is directly attached to the newly-formed hydroxylgroup has the (S) configuration.

In certain embodiments, the compound of formula (I) is a compound of theformula (I-AA):

or its pharmaceutically acceptable forms thereof,

and the compound of formula (II) is a compound of the formula(S)-(II-AA):

or its pharmaceutically acceptable forms thereof,

wherein R¹, R², R³, R⁵, R⁶, R¹⁰, R¹¹, R¹² and X are as defined herein.

In certain embodiments, the compound of formula (I) is a compound of theformula (I-BB):

or its pharmaceutically acceptable forms thereof,

and the compound of formula (II) is a compound of the formula(S)-(II-BB):

or its pharmaceutically acceptable forms thereof,

wherein R¹, R², R³, R⁵, R⁶ and X are as defined herein.

In certain embodiments, the compound of formula (I) is a compound of theformula (I-CC):

or its pharmaceutically acceptable forms thereof,

and the compound of formula (II) is a compound of the formula (II-CC):

or its pharmaceutically acceptable forms thereof,

wherein R¹ and X are as defined herein.

In another embodiment, the compounds of formulae (I) and (II) areselected from the set of compounds, or their pharmaceutically acceptableforms thereof, provided in Table 1.

In certain embodiments, the process preferentially generates a compoundof formula (II) of Table 1, or its pharmaceutically acceptable formsthereof, wherein the carbon atom that is directly attached to thenewly-formed hydroxyl group has the (S) configuration.

For example, in certain embodiments, the compounds of formulae (I) and(II) are selected from a set of compounds, or their pharmaceuticallyacceptable forms thereof, provided in Table 4, wherein the carbon atomthat is directly attached to the newly-formed hydroxyl group of thecompound of formula (II) has the (S) configuration:

TABLE 4 Compound of formula (I) Compound of formula (II)

(I-a)

(S)-(II-a)

(I-b)

(S)-(II-b)

(I-c)

(S)-(II-c)

(I-d)

(S)-(II-d)

In certain embodiments, the compound of formula (I) is a compound offormula (I-a)

or its pharmaceutically acceptable forms thereof,

and the compound of formula (II) is a compound of formula (S)-(II-a):

or its pharmaceutically acceptable forms thereof,

wherein R¹ is as defined herein, (see, e.g., FIG. 2).

In certain embodiments, R¹ is H.

In certain embodiments, R¹ is aralkyl (e.g., benzyl).

In certain embodiments, R¹ is —CO₂R¹⁶. In certain embodiments, R¹ is—CO₂R¹⁶ and R¹⁶ is alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycloalkyl, aralkyl, heteroaryl or heteroaralkyl. In certainembodiments, R¹ is a -Boc group (e.g., wherein R¹ is —CO₂R¹⁶ and R¹⁶ ist-butyl). In certain embodiments, R¹ is a -Cbz group (e.g., wherein R¹is —CO₂R¹⁶ and R¹⁶ is benzyl).

Ruthenium Transfer—Hydrogenation Catalysts

As generally defined above, provided herein is a process of preparing acompound of formula (II), or its pharmaceutically acceptable formsthereof, from a compound of formula (I), or its pharmaceuticallyacceptable forms thereof, the process comprising reacting a compound offormula (I), or its pharmaceutically acceptable forms thereof, with atransfer-hydrogenation catalyst in order to provide a compound offormula (II), or its pharmaceutically acceptable forms thereof.

Exemplary transfer-hydrogenation catalysts include, for example, iridiumtransfer-hydrogenation catalysts, ruthenium transfer-hydrogenationcatalysts and rhodium transfer-hydrogenation catalysts, e.g., asdescribed in Zassinovich and Mestroni, Chem. Rev. (1992) 92:1051-1069,the entirety of which is incorporated herein by reference.

In certain embodiments, the transfer-hydrogenation catalyst is aruthenium transfer-hydrogenation catalyst. Rutheniumtransfer-hydrogenation catalysts are described in, for example, U.S.Pat. Nos. 6,184,381, 6,887,820, T. Ikariya et al., Org. Biomol. Chem.(2006) 4:393-406 and Hashiguchi et al., J. Am. Chem. Soc. (1995)117:7562-7563 (“Noyori” ruthenium catalysts); U.S. Pat. Nos. 6,909,003;6,545,188; 7,250,526; 6,372,931; 6,509,467; 7,112,690; U.S. PatentApplication No. 2002/0193347 and Evaraere et al., Adv. Synth. Catal.(2003) 345:67-77 (“Carpentier” ruthenium catalysts); PCT application No.WO 2000/18708; PCT application No. WO 2001/09077; Reetz et al., J. Am.Chem. Soc. (2006) 1044-1045; Genov et al., Angew. Chem. (2004)43:2816-2819; Sasson and Blum, Tet. Lett. (1971) 24:2167; Mao et al.,Tet. Lett (2005) 46:7341-7344; H.-U. Blaser and H.-J. Federsel, Eds.,Asymmetric Catalysis on Industrial Scale, 2^(nd) edition, (2010)Wiley-VCH: A. J. Blacker, P. Thompson, Scale up Studies in AsymmetricTransfer Hydrogenation, pgs. 265-289, the entirety of each of which isincorporated herein by reference. Such references describe thepreparation and use of chiral ruthenium transfer-hydrogenationcatalysts.

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isa chiral ruthenium transfer-hydrogenation catalyst selected fromCl₃[((R)-tol-BINAP)RuCl]₂ ⁻Me₂NH₂ ⁺, Cl₃[((S)-tol-BINAP)RuCl]₂ ⁻Me₂NH₂⁺, ((R)-DIFLUORPHOS)RuCl₂(DMF)_(n), ((S)-DIFLUORPHOS)RuCl₂(DMF)_(n),((R)-DTBM-SEGPHOS)RuCl₂(p-cymene), ((S)-DTBM-SEGPHOS)RuCl₂(p-cymene),Cl₃[((R)-xylyl-SEGPHOS)RuCl]₂ ⁻Me₂NH₂ ⁺, Cl₃[((S)-xylyl-SEGPHOS)RuCl]₂⁻Me₂NH₂ ⁺, ((R)-xylyl-SEGPHOS)RuCl₂(R,R)DPEN,((S)-xylyl-SEGPHOS)RuCl₂(S,S)DPEN, (Ph₃P)RuCl₂((+)-(R)—Fe-oxazoline),(Ph₃P)RuCl₂((−)-(S)—Fe-oxazoline), ((S,R)JOSIPHOS)RuCl₂(DMF)_(n),((R,S)JOSIPHOS)RuCl₂(DMF)_(n),(11bS,11′bS)-4,4′-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis-dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepineand its enantiomer, (S,S)TsDPEN-RuCl(p-cymene),(S,S)TsDPEN-RuCl(hexamethylbenzene),(S,S)TsCyDN-RuCl(hexamethylbenzene),RuHCl(mesitylene)[(1S,2R)-ephedrine], RuHCl(hexamethylbenzene)[(1S,2R)-ephedrine], RuHCl(hexamethylbenzene) [(1R,2S)-ephedrine],RuHCl(p-cymene) [(1S,2R)-ephedrine], RuHCl(p-cymene)[(1R,2S)-ephedrine], RuHCl(benzene) [(1S,2R)-ephedrine],RuHCl(mesitylene) [(1R,2S)-2-methylaminocyclohexanol],RuHCl(hexamethylbenzene)[(1R,2S)2-methylaminocyclohexanol],RuHCl(hexamethylbenzene)[(1S,2S)2-methylaminocyclohexanol],RuHCl(p-cymene)[(1R,2S)-2-methylaminocyclohexanol], andRuHCl(benzene)[(1R,2S)2-methylaminocyclohexanol],RuHCl(hexamethylbenzene) [R-propranolol], RuHCl(hexamethylbenzene)[S-propranolol], RuHCl(hexamethylbenzene)[1R,2S-cis-1-amino-2-indanol],and RuHCl(hexamethylbenzene)[D-prolinol].

These ruthenium transfer-hydrogenation catalysts and others, both chiraland achiral, are further described below and herein.

Ligands Coordinated to the Catalyst

In certain embodiments, the ruthenium transfer-hydrogenation catalystcomprises one or more ligands.

Ligands can be classified as anionic (e.g., monoanionic, dianionic) orcharge-neutral (see Green, “A new approach to the formal classificationof covalent compounds of the elements” Journal of OrganometallicChemistry (1995) 500:127-148, incorporated herein by reference in itsentirety). Ligands can also be classified according to the “denticity”,i.e., to the number of times a ligand bonds to a metal throughnon-contiguous donor sites (represented by “κ^(n)” wherein “n” indicatesthe number of sites by which a ligand attaches to a metal). For example,a “monodentate” ligand (κ¹ ligand) refers to a ligand which bondsthrough one donor site, and a “bidentate” ligand (κ² ligand) refers to aligand which bonds through two non-contiguous donor sites. Ligands canfurther be classified according to the “hapticity” of the ligand, i.e.,the number of contiguous atoms that comprise a donor site and attach tothe metal center (represented by “η^(x)” wherein “x” indicates thenumber of contiguous atoms). For example, an aromatic 6-membered ring(e.g., a benzene ring) can exist as an η² ligand, η⁴ ligand or η⁶ liganddepending upon the number of pi (π) electrons used in forming thecoordinate bond.

Exemplary monoanionic monodentate ligands include, but are not limitedto, iodo (I⁻), bromo (Br⁻), chloro (Cl⁻), fluoro (F⁻), hydroxyl (HO⁻),cyano (CN⁻), nitro (NO₂ ⁻), isothiocyanato (SCN⁻) and S-thiocyanato(NCS⁻). In some embodiments, the monoanionic monodentate ligand ischloro (Cl⁻).

Exemplary monodentate neutral ligands include, but are not limited to,water (H₂O), acetonitrile (CH₃CN), ammonia (NH₃), carbon monoxide (CO),trimethylphosphine (PMe₃), tricyclohexylphosphine (PCy₃),triphenylphosphine (PPh₃), tri(o-tolyl)phosphine (P(o-tolyl)₃) andpyridine (C₅H₅N). In some embodiments, the monodentate neutral ligand isselected from trimethylphosphine (PMe₃), tricyclohexylphosphine (PCy₃),and triphenylphosphine (PPh₃).

Exemplary bidentate neutral ligands include, but are not limited to,2,2′bipyridine, 1,10-phenanthroline, bisphosphino ligands (e.g.,1,2-bis(diphenylphosphino)ethane, 1,2-bis(diphenylphosphino)methane),diamine ligands (e.g., ethylenediamine) and amino alcohol ligands.

Exemplary η^(x) neutral ligands include, but are not limited to,optionally substituted benzene ligands, e.g., benzene (C₆H₆), toluene(C₆H₅CH₃), xylene (e.g., o-xylene, m-xylene, p-xyelene), cymene (e.g.,o-cymene, m-cymene, p-cymene), mesitylene and hexamethylbenzene. In someembodiments, the η^(x) neutral ligand is selected from optionallysubstituted benzene (C₆H₆), p-cymene, mesitylene, and hexamethylbenzene.

In certain embodiments, the ruthenium transfer-hydrogenation catalystcomprises at least one ligand selected from an amino alcohol ligand, amonoanionic monodentate ligand and an optionally substituted benzeneligand. Such ligands will be further described below and herein.

Monodentate and Bidentate Neutral Ligands

In certain embodiments, the ruthenium transfer-hydrogenation catalystcomprises one or more monodentate or bidentate ligands. In someembodiments, these ligands can render chirality to the rutheniumtransfer-hydrogenation catalyst. In other embodiments, these ligandsgenerate an achiral ruthenium transfer-hydrogenation catalyst.

Exemplary monodentate phosphine ligands include, but are not limited to,trimethylphosphine (PMe₃), tricyclohexylphosphine (PCy₃),triphenylphosphine (PPh₃), tri(o-tolyl)phosphine (P(o-tolyl)₃),(S)—Fe-oxazoline, and (R)—Fe-oxazoline. Non-limiting examples ofbidentate bisphosphino ligands include 1,2-bis(diphenylphosphino)ethane,1,2-bis(diphenylphosphino)methane, (R)-tol-BINAP, (S)-tol-BINAP,(R)-DIFLUORPHOS), (S)-DIFLUORPHOS, (R)-DTBM-SEGPHOS, (S)-DTBM-SEGPHOS,(S,R)JOSIPHOS), (R,S)JOSIPHOS),4,4′-(9,9-dimethyl-9H-xanthene-4,5-diyl)didinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine,and(11bS,11′bS)-4,4′-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis-dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepineand its enantiomer.

In addition to the monodentate neutral ligand NH₃, other suchmonodentate amino ligands include, but are not limited to, unsubstitutedor substituted alkyl, perhaloalkyl, alkenyl, alkynyl, cycloalkyl, aryl,or aralkyl amines. Exemplary alkyl amines include, but are not limitedto, methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl,n-pentyl, isopentyl, and n-hexyl amine, or substituted variants thereof.Unsubstituted or substituted cycloalkyl amines include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl amines. Unsubstituted or substituted arylamines and heteroaromatics include, but are not limited to, aniline,pyridine, pyrimidine.

Exemplary bidentate amino ligands include, but are not limited to,unsubstituted or substituted 2,2′bipyridine, ethylenediamine,propylenediamine, o-cyclopentyldiamine, o-cyclohexyldiamine,(R,R)-TsDPEN, (R,S)-TsDPEN, (S,R)-TsDPEN, (S,S)-TsDPEN, (R,R)-MsDPEN,(R,S)-MsDPEN, (S,R)-MsDPEN, and (S,S)-MsDPEN.

Exemplary methods for preparing ruthenium transfer-hydrogenationcatalysts employing these phosphino and amino neutral ligands can befound, e.g., in the references detailed above.

Amino Alcohol Ligands

In certain embodiments, the ruthenium transfer-hydrogenation catalystcomprises an amino alcohol ligand.

In certain embodiments, the amino alcohol ligand is of the formula(i-a):

or its pharmaceutically acceptable forms thereof,

wherein each R^(a) and R^(b) are independently selected from hydrogen,alkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, or R^(a)and R^(b) are joined to form a 3-8 membered carbocyclic or heterocyclicring system;

and R^(c) is selected from alkyl, perhaloalkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl,and heteroaralkyl.

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isan achiral ruthenium transfer-hydrogenation catalyst.

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isan achiral ruthenium transfer-hydrogenation catalyst comprising an aminoalcohol ligand of the formula (i-a) where R^(a) and R^(b) are the samegroup. For example, in certain embodiments, R^(a) and R^(b) are the samegroup selected from C₁₋₆ alkyl and C₁₋₆ perhaloalkyl. In certainembodiments, R^(a) and R^(b) are the same group selected from C₁₋₆alkyl. In certain embodiments, R^(a) and R^(b) are both —CH₃.

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isa chiral ruthenium transfer-hydrogenation catalyst.

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isa chiral ruthenium transfer-hydrogenation catalyst comprising an aminoalcohol ligand of the formula (i-a). For example, in certainembodiments, R^(a) is hydrogen and R^(b) is C₁₋₆ alkyl, or R^(b) ishydrogen and R^(a) is C₁₋₆ alkyl. In certain embodiments, R^(a) ishydrogen and R^(b) is C₁₋₆ alkyl, or R^(b) is hydrogen and R^(a) is C₁₋₆alkyl.

In certain embodiments, R^(a) is selected from alkyl and perhaloalkyl.In certain embodiments, R^(a) is selected from C₁₋₆ alkyl (e.g., methyl,ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl,isopentyl, n-hexyl) and C₁₋₆ perhaloalkyl (e.g., —CF₃, —CCl₃, —CBr₃,—CF₂CF₃, etc). In certain embodiments, R^(a) is C₁₋₆ alkyl (e.g.,methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl,n-pentyl, isopentyl, n-hexyl). In certain embodiments, R^(a) is C₁₋₆perhaloalkyl (e.g., —CF₃, —CCl₃, —CBr₃, —CF₂CF₃, etc). In certainembodiments, R^(a) is methyl (—CH₃) or perfluoromethyl (—CF₃). Incertain embodiments, R^(a) is methyl (—CH₃). In certain embodiments,R^(a) is perfluoromethyl (—CF₃).

For example, in certain embodiments, wherein R^(a) is methyl, the aminoalcohol ligand is of the formula (i-b):

wherein R^(b) and R^(c) are as defined above and herein.

In certain embodiments, R^(b) is selected from alkyl and perhaloalkyl.In certain embodiments, R^(b) is selected from C₁₋₆ alkyl (e.g., methyl,ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl,isopentyl, n-hexyl) and C₁₋₆ perhaloalkyl (e.g., —CF₃, —CCl₃, —CBr₃,—CF₂CF₃, etc). In certain embodiments, R^(b) is selected from C₁₋₆ alkyl(e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl,n-pentyl, isopentyl, n-hexyl). In certain embodiments, R^(b) is selectedfrom C₁₋₆ perhaloalkyl (e.g., —CF₃, —CCl₃, —CBr₃, —CF₂CF₃, etc). Incertain embodiments, R^(b) is methyl (—CH₃) or perfluoromethyl (—CF₃).In certain embodiments, R^(b) is methyl (—CH₃). In certain embodiments,R^(b) is perfluoromethyl (—CF₃).

For example, in certain embodiments, wherein R^(b) is methyl, the aminoalcohol ligand is of the formula (i-c):

wherein R^(a) and R^(c) are as defined above and herein.

In certain embodiments, R^(c) is alkyl. In certain embodiments, R^(c) isC₁₋₆ alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl,sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl). In certainembodiments, R^(c) is C₁₋₃ alkyl (e.g., methyl, ethyl, isopropyl,n-propyl). In certain embodiments, R^(c) is ethyl (—CH₂CH₃).

For example, in certain embodiments, wherein R^(c) is ethyl, the aminoalcohol ligand is of the formula (i-d):

wherein R^(a) and R^(b) are as defined above and herein.

In certain embodiments, wherein R^(a) is methyl and R^(c) is ethyl, theamino alcohol ligand is of the formula (i-e):

wherein R^(b) is as defined above and herein.

In certain embodiments, wherein R^(b) is methyl and R^(c) is ethyl, theamino alcohol ligand is of the formula (i-f):

wherein R^(a) is as defined above and herein.

In certain embodiments, the amino alcohol of formula (i-a) is a chiralamino alcohol, which contains at least one asymmetric center). Forexample, in certain embodiments, R^(a) and R^(b) are different groups orat least one of R^(a), R^(b) or R^(c) contains at least one asymmetriccenter. In certain embodiments, wherein the amino alcohol of formula(i-a) is a chiral amino alcohol, the ruthenium transfer-hydrogenationcatalyst is also a chiral ruthenium transfer-hydrogenation catalyst.

In certain embodiments, wherein the amino alcohol of formula (i-a) is achiral amino alcohol, R^(a) and R^(b) are different groups. For example,in certain embodiments, R^(a) is hydrogen and R^(b) is alkyl,perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. Incertain embodiments, R^(a) is hydrogen and R^(b) is C₁₋₆ alkyl (e.g.,methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl,n-pentyl, isopentyl, n-hexyl) or C₁₋₆ perhaloalkyl (e.g., —CF₃, —CCl₃,—CBr₃, —CF₂CF₃, etc). In certain embodiments, R^(a) is hydrogen andR^(b) is C₁₋₆ alkyl. In certain embodiments, R^(a) is hydrogen and R^(b)is methyl (—CH₃).

For example, in certain embodiments, wherein R^(a) is hydrogen and R^(b)is methyl, the amino alcohol ligand is of the formula (i-g):

wherein R^(c) is as defined above and herein.

In other embodiments, wherein the amino alcohol of formula (i-a) is achiral amino alcohol, R^(b) is hydrogen and R^(a) is alkyl,perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. Incertain embodiments, R^(b) is hydrogen and R^(a) is C₁₋₆ alkyl (e.g.,methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl,n-pentyl, isopentyl, n-hexyl) or C₁₋₆ perhaloalkyl (e.g., —CF₃, —CCl₃,—CBr₃, —CF₂CF₃, etc). In certain embodiments, R^(b) is hydrogen andR^(a) is C₁₋₆ alkyl. In certain embodiments, R^(b) is hydrogen and R^(a)is methyl (—CH₃).

For example, in certain embodiments, wherein R^(a) is methyl and R^(b)is hydrogen, the amino alcohol ligand is of the formula (i-h):

wherein R^(c) is as defined above and herein.

However, in certain embodiments, the amino alcohol of formula (i-a) isan achiral amino alcohol, which does not contain an asymmetric center).For example, in certain embodiments, both R^(a) and R^(b) are the samegroup selected from alkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, andheteroaralkyl, or R^(a) and R^(b) are joined to form a 3-8 memberedcarbocyclic or heterocyclic ring system provided that R^(a) and R^(b) orthe joined ring do not contain an asymmetric center. In certainembodiments, wherein the amino alcohol of formula (i-a) is an achiralamino alcohol, the ruthenium transfer-hydrogenation catalyst is anachiral ruthenium transfer-hydrogenation catalyst.

In certain embodiments wherein the amino alcohol of formula (i-a) is anachiral amino alcohol, both R^(a) and R^(b) are the same group selectedfrom alkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. Incertain embodiments, both R^(a) and R^(b) are the same group selectedfrom alkyl and perhaloalkyl. In certain embodiments, both R^(a) andR^(b) are the same group selected from C₁₋₆ alkyl (e.g., methyl, ethyl,isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl,n-hexyl) and C₁₋₆ perhaloalkyl (e.g., —CF₃, —CCl₃, —CBr₃, —CF₂CF₃, etc).In certain embodiments, both R^(a) and R^(b) are the same group selectedfrom C₁₋₆ alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl,sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl). In certainembodiments, both R^(a) and R^(b) are the same group selected from C₁₋₆perhaloalkyl (e.g., —CF₃, —CCl₃, —CBr₃, —CF₂CF₃, etc). In certainembodiments, both R^(a) and R^(b) are the same group selected frommethyl (—CH₃) and perfluoromethyl (—CF₃). In certain embodiments, bothR^(a) and R^(b) are methyl (—CH₃). In certain embodiments, both R^(a)and R^(b) are perfluoromethyl (—CF₃).

For example, in certain embodiments, wherein both R^(a) and R^(b) aremethyl, the amino alcohol ligand is of the formula (i-i):

wherein R^(c) is as defined above and herein.

In some embodiments, R^(c) is hydrogen. In some embodiments, R^(c) isC₁₋₆alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl). Insome embodiments, R^(c) is methyl. In some embodiments, R^(c) is ethyl.In some embodiments, R^(c) is propyl. In some embodiments, R^(c) isisopropyl.

For example, in certain embodiments, the amino alcohol is of the formula(i-j):

In certain embodiments wherein the amino alcohol of formula (i-a) is anachiral amino alcohol, R^(a) and R^(b) are joined to form a 3-8 memberedcarbocyclic or heterocyclic ring system provided that the joined ringdoes not contain an asymmetric center.

For example, in certain embodiments, R^(a) and R^(b) are joined to forma 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring system providedthat the joined ring does not contain an asymmetric center. In certainembodiments, R^(a) and R^(b) are joined to form a 3-, 4-, 5-, 6-, 7-, or8-membered carbocyclic ring system selected from:

wherein R^(c) is as defined above and herein.

In certain embodiments, R^(a) and R^(b) are joined to form a 4-, 6- or8-membered heterocyclic ring system provided that the joined ring doesnot contain an asymmetric center. In certain embodiments, R^(a) andR^(b) are joined to form a 4-, 6- or 8-membered heterocyclic ring systemselected from:

wherein R^(c) is as defined above and herein,

R^(c) is a group selected from H, alkyl, perhaloalkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl,and heteroaralkyl, and

both R^(f) and R^(g) are the same group selected from alkyl,perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl,

provided that the groups R^(e), R^(f) and R^(g) do not contain anasymmetric center.

In some embodiments, R^(a) and R^(b) are joined to form a 4-, 6- or8-membered heterocyclic ring system where the joined ring does containan asymmetric center. In certain embodiments, R^(a) and R^(b) are joinedto form a 4-, 6- or 8-membered heterocyclic ring system selected from:

wherein R^(c) is as defined above and herein, and

R^(e) is a group selected from H, alkyl, perhaloalkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl,and heteroaralkyl.

In certain embodiments, both R^(f) and R^(g) are the same group selectedfrom alkyl and perhaloalkyl. In certain embodiments, both R^(f) andR^(g) are the same group selected from C₁₋₆ alkyl (e.g., methyl, ethyl,isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl,n-hexyl) and C₁₋₆ perhaloalkyl (e.g., —CF₃, —CCl₃, —CBr₃, —CF₂CF₃, etc).In certain embodiments, both R^(f) and R^(g) are the same group selectedfrom C₁₋₆ alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl,sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl). In certainembodiments, both R^(f) and R^(g) are the same group selected from C₁₋₆perhaloalkyl (e.g., —CF₃, —CCl₃, —CBr₃, —CF₂CF₃, etc). In certainembodiments, both R^(f) and R^(g) are the same group selected frommethyl (—CH₃) and perfluoromethyl (—CF₃). In certain embodiments, bothR^(f) and R^(g) are methyl (—CH₃). In certain embodiments, both R^(f)and R^(g) are perfluoromethyl (—CF₃).

In some embodiments, the amino alcohol ligand is of Formula (i-z):

or its pharmaceutically acceptable forms thereof,

wherein each R^(a) and R^(b) are independently selected from hydrogen,alkyl, perhaloalkyl, aryloxyalkyl, alkenyl, alkynyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, andheteroaralkyl, or R^(a) and R^(b) are joined to form a 3-10 memberedcarbocyclic or heterocyclic ring system;

each R^(n) and R^(o) are independently selected from hydrogen, alkyl,aryloxyalkyl, perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, or R^(n)and R^(o) are joined to form a 3-10 membered carbocyclic or heterocyclicring system; or

R^(a) and R^(n) are joined together to form a 3-10 membered carbocyclicor heterocyclic ring system and R^(b) and R^(o) are each hydrogen; or

R^(a) and R^(o) are joined together to form a 3-10 membered carbocyclicor heterocyclic ring system and R^(b) and R^(n) are each hydrogen; or

R^(b) and R^(o) are joined together to form a 3-10 membered carbocyclicor heterocyclic ring system and R^(a) and R^(n) are each hydrogen; or

R^(b) and R^(n) are joined together to form a 3-10 membered carbocyclicor heterocyclic ring system and R^(a) and R^(o) are each hydrogen; and

R^(c) i selected from alkyl, perhaloalkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl,and heteroaralkyl; or

R^(a) and R^(c) are joined together to form a 3-10 membered carbocyclicor heterocyclic ring system and R^(b) is hydrogen; or

R^(b) and R^(c) are joined together to form a 3-10 membered carbocyclicor heterocyclic ring system and R^(a) is hydrogen.

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isa chiral ruthenium transfer-hydrogenation catalyst comprising an aminoalcohol ligand of the formula (i-z). For example, in certainembodiments, R^(a) is hydrogen and R^(b) is C₁₋₆ alkyl, or R^(b) ishydrogen and R^(a) is C₁₋₆ alkyl. In certain embodiments, R^(a) ishydrogen and R^(b) is Me, or R^(b) is hydrogen and R^(a) is Me. Incertain embodiments, R^(n) is aryl and R^(o) is hydrogen, or R^(o) ishydrogen and R^(n) is aryl. In certain embodiments, R^(n) is phenyl andR^(o) is hydrogen, or R^(o) is hydrogen and R^(n) is phenyl.

In certain embodiments, R^(a) is selected from alkyl and perhaloalkyl.In certain embodiments, R^(a) is selected from C₁₋₆alkyl (e.g., methyl,ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl,isopentyl, n-hexyl) and C₁₋₆ perhaloalkyl (e.g., —CF₃, —CCl₃, —CBr₃,—CF₂CF₃, etc). In certain embodiments, R^(a) is C₁₋₆ alkyl (e.g.,methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl,n-pentyl, isopentyl, n-hexyl). In certain embodiments, R^(a) is C₁₋₆perhaloalkyl (e.g., —CF₃, —CCl₃, —CBr₃, —CF₂CF₃, etc). In certainembodiments, R^(a) is methyl (—CH₃) or perfluoromethyl (—CF₃). Incertain embodiments, R^(a) is methyl (—CH₃). In certain embodiments,R^(a) is perfluoromethyl (—CF₃).

In certain embodiments, R^(b) is selected from alkyl and perhaloalkyl.In certain embodiments, R^(b) is selected from C₁₋₆ alkyl (e.g., methyl,ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl,isopentyl, n-hexyl) and C₁₋₆ perhaloalkyl (e.g., —CF₃, —CCl₃, —CBr₃,—CF₂CF₃, etc). In certain embodiments, R^(b) is selected from C₁₋₆ alkyl(e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl,n-pentyl, isopentyl, n-hexyl). In certain embodiments, R^(b) is selectedfrom C₁₋₆ perhaloalkyl (e.g., —CF₃, —CCl₃, —CBr₃, —CF₂CF₃, etc). Incertain embodiments, R^(b) is methyl (—CH₃) or perfluoromethyl (—CF₃).In certain embodiments, R^(b) is methyl (—CH₃). In certain embodiments,R^(b) is perfluoromethyl (—CF₃).

In certain embodiments, R^(n) is selected from alkyl and perhaloalkyl.In certain embodiments, R^(n) is selected from C₁₋₆ alkyl (e.g., methyl,ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl,isopentyl, n-hexyl) and C₁₋₆ perhaloalkyl (e.g., —CF₃, —CCl₃, —CBr₃,—CF₂CF₃, etc). In certain embodiments, R^(n) is selected from C₁₋₆ alkyl(e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl,n-pentyl, isopentyl, n-hexyl). In certain embodiments, R^(n) is selectedfrom C₁₋₆ perhaloalkyl (e.g., —CF₃, —CCl₃, —CBr₃, —CF₂CF₃, etc). Incertain embodiments, R^(n) is methyl (—CH₃) or perfluoromethyl (—CF₃).In certain embodiments, R^(n) is methyl (—CH₃). In certain embodiments,R^(a) is perfluoromethyl (—CF₃).

In certain embodiments, R^(o) is selected from alkyl and perhaloalkyl.In certain embodiments, R^(o) is selected from C₁₋₆ alkyl (e.g., methyl,ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl,isopentyl, n-hexyl) and C₁₋₆ perhaloalkyl (e.g., —CF₃, —CCl₃, —CBr₃,—CF₂CF₃, etc). In certain embodiments, R^(o) is selected from C₁₋₆ alkyl(e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl,n-pentyl, isopentyl, n-hexyl). In certain embodiments, R^(o) is selectedfrom C₁₋₆ perhaloalkyl (e.g., —CF₃, —CCl₃, —CBr₃, —CF₂CF₃, etc). Incertain embodiments, R^(o) is methyl (—CH₃) or perfluoromethyl (—CF₃).In certain embodiments, R^(o) is methyl (—CH₃). In certain embodiments,R^(o) is perfluoromethyl (—CF₃).

In certain embodiments, R^(a) is hydrogen and R^(b) is C₁₋₆ alkyl orR^(b) is hydrogen and R^(a) is C₁₋₆ alkyl, and R^(n) and R^(o) are eachhydrogen.

In certain embodiments, R^(c) is alkyl. In certain embodiments, R^(c) isC₁₋₆ alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl,sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl). In certainembodiments, R^(c) is C₁₋₃ alkyl (e.g., methyl, ethyl, isopropyl,n-propyl). In certain embodiments, R^(c) is ethyl (—CH₂CH₃).

In certain embodiments, the amino alcohol of formula (i-z) is a chiralamino alcohol (i.e., the amino alcohol contains at least one asymmetriccenter). For example, in certain embodiments, R^(a) and R^(b) aredifferent groups, R^(n) and R^(o) are different groups, or at least oneof R^(a), R^(b), R^(n), R^(o) or R^(c) contains at least one asymmetriccenter. In certain embodiments, wherein the amino alcohol of formula(i-z) is a chiral amino alcohol, the ruthenium transfer-hydrogenationcatalyst is also a chiral ruthenium transfer-hydrogenation catalyst.

In certain embodiments, wherein the amino alcohol of formula (i-z) is achiral amino alcohol, R^(a) and R^(b) are different groups. In certainembodiments, wherein the amino alcohol of formula (i-z) is a chiralamino alcohol, R^(a) and R^(b) are different groups. For example, incertain embodiments, R^(a) is hydrogen and R^(b) is alkyl, perhaloalkyl,alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aralkyl, or heteroaralkyl. In certain embodiments, R^(a) ishydrogen and R^(b) is C₁₋₆ alkyl (e.g., methyl, ethyl, isopropyl,n-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl) orC₁₋₆ perhaloalkyl (e.g., —CF₃, —CCl₃, —CBr₃, —CF₂CF₃, etc). In certainembodiments, R^(a) is hydrogen and R^(b) is C₁₋₆ alkyl. In certainembodiments, R^(a) is hydrogen and R^(b) is methyl (—CH₃).

In certain embodiments, R^(b) is hydrogen and R^(a) is alkyl,perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. Incertain embodiments, R^(b) is hydrogen and R^(a) is C₁₋₆ alkyl (e.g.,methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl,n-pentyl, isopentyl, n-hexyl) or C₁₋₆ perhaloalkyl (e.g., —CF₃, —CCl₃,—CBr₃, —CF₂CF₃, etc). In certain embodiments, R^(b) is hydrogen andR^(a) is C₁₋₆ alkyl. In certain embodiments, R^(b) is hydrogen and R^(a)is methyl (—CH₃).

In other embodiments, R^(n) is hydrogen and R^(o) is alkyl,perhaloalkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. Incertain embodiments, R^(o) is hydrogen and R^(n) is C₁₋₆ alkyl (e.g.,methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl,n-pentyl, isopentyl, n-hexyl) or C₁₋₆ perhaloalkyl (e.g., —CF₃, —CCl₃,—CBr₃, —CF₂CF₃, etc). In certain embodiments, R^(n) is hydrogen andR^(o) is C₁₋₆ alkyl. In certain embodiments, R^(n) is hydrogen and R^(o)is methyl (—CH₃). In certain embodiments, R^(o) is hydrogen and R^(n) isC₁₋₆ alkyl. In certain embodiments, R^(o) is hydrogen and R^(n) ismethyl (—CH₃).

In certain embodiments, R^(a), R^(b) and R^(n) are each hydrogen, R^(c)is alkyl (e.g., isopropyl), and R^(o) is substituted alkyl, such as, butnot limited to, aryloxyalkyl (e.g., naphthyloxymethyl). In otherembodiments, R^(a), R^(b) and R^(o) are each hydrogen, R^(c) is alkyl(e.g., isopropyl), and R^(n) is substituted alkyl, such as, but notlimited to, aryloxyalkyl (e.g., naphthyloxymethyl).

In some embodiments, the amino alcohol ligand of Formula (i-z) is(+)-(1S,2R)ephedrine, (−)-(1R,2S)ephedrine, (+)-(1S,2S)pseudoephedrine,or (−)-(1R,2R) pseudoephedrine. In some embodiments, the amino alcoholligand is (+)-(1S,2R)ephedrine. In some embodiments, the amino alcoholligand is (−)-(1R,2S)ephedrine.

In some embodiments, R^(a) and R^(n) are joined together to form a 3-10membered carbocyclic or heterocyclic ring system and R^(b) and R^(o) areeach hydrogen. In some embodiments, R^(a) and R^(o) are joined togetherto form a 3-10 membered carbocyclic or heterocyclic ring system andR^(b) and R^(n) are each hydrogen. In other embodiments, R^(b) and R^(o)are joined together to form a 3-10 membered carbocyclic or heterocyclicring system and R^(a) and R^(n) are each hydrogen. In certainembodiments, R^(b) and R^(n) are joined together to form a 3-10 memberedcarbocyclic or heterocyclic ring system and R^(a) and R^(o) are eachhydrogen. Exemplary 3-10 monocyclic carbocyclic ring systems include,but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyland cyclooctyl rings. Exemplary 3-10 bicyclic carbocyclic ring systemsinclude bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl,octahydro-1H-indenyl, decahydronaphthalenyl, and spiro[4.5]decanyl.

In one embodiment, R^(a) and R^(o) are joined together to form acyclohexyl ring system, R^(b) and R^(n) are each hydrogen, and R^(c) isC₁₋₆alkyl (e.g., Me). In another embodiment, R^(b) and R^(n) are joinedtogether to form a cyclohexyl ring system, R^(a) and R^(o) are eachhydrogen, and R^(c) is C₁₋₆alkyl (e.g., Me). In another embodiment,R^(a) and R^(n) are joined together to form a cyclohexyl ring system,R^(b) and R^(o) are each hydrogen, and R^(c) is C₁₋₆alkyl (e.g., Me). Inanother embodiment, R^(b) and R^(o) are joined together to form acyclohexyl ring system, R^(a) and R^(n) are each hydrogen, and R^(c) isC₁₋₆alkyl (e.g., Me). In another embodiment, R^(a) and R^(n) are joinedtogether to form a octahydro-1H-indenyl ring system, R^(b) and R^(o) areeach hydrogen, and R^(c) is hydrogen. In another embodiment, R^(b) andR^(o) are joined together to form a octahydro-1H-indenyl ring system,R^(a) and R^(n) are each hydrogen, and R^(c) is hydrogen. In someembodiments, R^(a) and R^(c) are joined together to form a 3-10 memberedcarbocyclic ring system (e.g., cyclopentyl) and R^(b), R^(n) and R^(o)are each hydrogen. In some embodiments, R^(b) and R^(c) are joinedtogether to form a 3-10 membered carbocyclic ring system (e.g.,cyclopentyl) and R^(a), R^(n) and R^(o) are each hydrogen.

Optionally Substituted Benzene Ligands

In certain embodiments, the ruthenium transfer-hydrogenation catalystcomprises an optionally substituted benzene ligand.

In certain embodiments, the optionally substituted benzene ligand is ofthe formula (ii-a):

wherein each R^(h), R^(i), R^(j), R^(k), R^(l), and R^(m) areindependently selected from hydrogen, alkyl, perhaloalkyl, alkenyl,alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,aralkyl, and heteroaralkyl.

In certain embodiments, each R^(h), R^(i), R^(j), R^(k), R^(l), andR^(m) are independently selected from hydrogen, alkyl and perhaloalkyl.In certain embodiments, each R^(h), R^(i), R^(j), R^(k), R^(l), andR^(m) are independently selected from hydrogen, C₁₋₆ alkyl (e.g.,methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, t-butyl,n-pentyl, isopentyl, n-hexyl) and C₁₋₆ perhaloalkyl (e.g., —CF₃, —CCl₃,—CBr₃, —CF₂CF₃, etc). In certain embodiments, each R^(h), R^(i), R^(j),R^(k), R^(l), and R^(m) are independently selected from hydrogen andC₁₋₆ alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl,sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl). In certainembodiments, each R^(h), R^(i), R^(j), R^(k), R^(l), and R^(m) areindependently selected from hydrogen and C₁₋₆ perhaloalkyl (e.g., —CF₃,—CCl₃, —CBr₃, —CF₂CF₃, etc). In certain embodiments, each R^(h), R^(i),R^(j), R^(k), R^(l), and R^(m) are independently selected from hydrogen,methyl (—CH₃) and perfluoromethyl (—CF₃). In certain embodiments, eachR^(h), R^(i), R^(j), R^(k), R^(l), and R^(m) are independently selectedfrom hydrogen and methyl (—CH₃). In certain embodiments, each R^(h),R^(i), R^(j), R^(k), R^(l), and R^(m) are independently selected fromhydrogen and perfluoromethyl (—CF₃).

For example, in certain embodiments, wherein each R^(h), R^(i), R^(j),R^(k), R^(l), and R^(m) are independently selected from hydrogen andC₁₋₆ alkyl, the optionally substituted benzene ligand is selected fromany one of the following ligands:

In some embodiments, the optionally substituted benzene ligand isselected from any one of the following ligands:

In certain embodiments, the hapticity of the optionally substitutedbenzene ligand is η². In certain embodiments, the hapticity of theoptionally substituted benzene ligand is η⁴. In certain embodiments, thehapticity of the optionally substituted benzene ligand hapticity is η⁶.

In certain embodiments, the optionally substituted benzene ligand isη⁶-hexamethylbenzene.

Monoanionic Monodentate Ligands

In certain embodiments, the ruthenium transfer-hydrogenation catalystincludes a monoanionic monodentate ligand. Exemplary monoanionicmonodentate ligands include, but are not limited to, halo (e.g., iodo(I⁻), bromo (Br⁻), chloro (Cl⁻) and fluoro (F⁻)), hydroxyl (HO⁻), cyano(CN⁻), nitro (NO₂ ⁻), isothiocyanato (SCN⁻) and S-thiocyanato (NCS⁻)ligands.

For example, in certain embodiments, the rutheniumtransfer-hydrogenation catalyst comprises a halo ligand. In certainembodiments, the halo ligand is iodo (I⁻), bromo (Br⁻), or chloro (Cl⁻).In certain embodiments, the halo ligand is chloro (Cl⁻).

Ruthenium Transfer-Hydrogenation Catalyst

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isa chiral ruthenium transfer-hydrogenation catalyst. In some embodiments,the ruthenium transfer-hydrogenation catalyst is selected from(S,S)TsDPEN-RuCl(p-cymene), ((S,R)JOSIPHOS)RuCl2(DMF)n,((R,S)JOSIPHOS)RuCl2(DMF)n,(11bS,11′bS)-4,4′-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis-dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepineand its enantiomer, RuHCl(mesitylene) [(1S,2R)-ephedrine],RuHCl(hexamethylbenzene)[(1S,2R)-ephedrine],RuHCl(hexamethylbenzene)[(1R,2S)-ephedrine],RuHCl(p-cymene)[(1R,2S)2-methylaminocyclohexanol],RuHCl(hexamethylbenzene)[R-propranolol],RuHCl(hexamethylbenzene)[1R,2S-cis-1-amino-2-indanol],RuHCl(hexamethylbenzene)[(1R,2S)2-methylaminocyclohexanol],RuHCl(hexamethylbenzene)[(1S,2S)2-methylaminocyclohexanol],RuHCl(hexamethylbenzene) [R-propranolol], RuHCl(hexamethylbenzene)[S-propranolol], and (S,S)TsDPEN-RuCl(hexamethylbenzene).

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isan achiral ruthenium transfer-hydrogenation catalyst.

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isof the formula (iii-a):

wherein R^(a), R^(b), R^(c), R^(h), R^(i), R^(j), R^(k), R^(l), andR^(m) are as defined above and herein.

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isof the formula (iii-a):

wherein R^(a) and R^(b) are the same group selected from C₁₋₆ alkyl andC₁₋₆ perhaloalkyl, or R^(a) and R^(b) are joined to form a 3-8 memberedcarbocyclic or heterocyclic ring system;

R^(c) is selected from C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, aralkyl,heteroaralkyl, aryl and heteroaryl; and

each R^(h), R^(i), R^(j), R^(k), R^(l), and R^(m) are independentlyselected from hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl,carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl.

In certain embodiments, wherein R^(a) is methyl, the rutheniumtransfer-hydrogenation catalyst is of the formula (iii-b):

wherein R^(b), R^(c), R^(h), R^(i), R^(j), R^(k), R^(l), and R^(m) areas defined above and herein

In certain embodiments, wherein R^(b) is methyl, the rutheniumtransfer-hydrogenation catalyst is of the formula (iii-c):

wherein R^(a), R^(c), R^(h), R^(i), R^(j), R^(k), R^(l), and R^(m) areas defined above and herein.

In certain embodiments, wherein R^(c) is ethyl, the rutheniumtransfer-hydrogenation catalyst is of the formula (iii-d):

wherein R^(a), R^(b), R^(h), R^(i), R^(j), R^(k), R^(l), and R^(m) areas defined above and herein.

In certain embodiments, wherein both R^(a) and R^(b) are methyl, theruthenium transfer-hydrogenation catalyst is of the formula (iii-e):

wherein R^(c), R^(h), R^(i), R^(j), R^(k), R^(l), and R^(m) are asdefined above and herein.

In certain embodiments, wherein both R^(a) and R^(b) are methyl andR^(c) is ethyl, the ruthenium transfer-hydrogenation catalyst is of theformula (iii-f):

wherein R^(h), R^(i), R^(j), R^(l), and R^(m) are as defined above andherein.

For example, in certain embodiments, the rutheniumtransfer-hydrogenation catalyst is an achiral catalyst of the formula(iii-g):

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isof the formula (iii-h):

wherein each R^(a), R^(b), R^(n) and R^(o) are independently selectedfrom hydrogen, alkyl, aryloxyalkyl, aryl, and perhaloalkyl, or

R^(a) and R^(n) are joined together to form a 3-10 membered carbocyclicor heterocyclic ring system and R^(b) and R^(o) are each hydrogen; or

R^(a) and R^(o) are joined together to form a 3-10 membered carbocyclicor heterocyclic ring system and R^(b) and R^(n) are each hydrogen; or

R^(b) and R^(o) are joined together to form a 3-10 membered carbocyclicor heterocyclic ring system and R^(a) and R^(n) are each hydrogen; or

R^(b) and R^(n) are joined together to form a 3-10 membered carbocyclicor heterocyclic ring system and R^(a) and R^(o) are each hydrogen; and

R^(c) is selected from C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, aralkyl,heteroaralkyl, aryl and heteroaryl; and

each R^(h), R^(i), R^(j), R^(k), R^(l), and R^(m) are independentlyselected from hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl,carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl.

In some embodiments, to form the ruthenium transfer hydrogenationcatalyst, the Ru starting material is an (arene)Ru(X_(a)) dimer, such as(v-a):

wherein R^(h), R^(i), R^(j), R^(k), R^(l), and R^(m) are as definedabove and herein, and

X^(a) is selected from halo (e.g., iodo (I⁻), bromo (Br⁻), chloro (Cl⁻)and fluoro (F⁻)).

In certain embodiments, X^(a) is selected from iodo (I⁻), bromo (Br⁻),and chloro(Cl⁻). In certain embodiments, X^(a) is chloro (Cl⁻). In someembodiments, each R^(h), R^(i), R^(j), R^(k), R^(l), and R^(m) areindependently selected from hydrogen, alkyl, perhaloalkyl, alkenyl,alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,aralkyl, and heteroaralkyl. In certain embodiments, each R^(h), R^(i),R^(j), R^(k), R^(l), and R^(m) are independently selected from hydrogen,C₁₋₆ alkyl (e.g., methyl, ethyl, isopropyl, n-propyl, n-butyl,sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl) and C₁₋₆ perhaloalkyl(e.g., —CF₃, —CCl₃, —CBr₃, —CF₂CF₃, etc). In certain embodiments, eachR^(h), R^(i), R^(j), R^(k), R^(l), and R^(m) are independently selectedfrom hydrogen and methyl (—CH₃). In some embodiments, the optionallysubstituted arene ring is selected from benzene, toluene, o-xylene,m-xylene, p-xylene, mesitylene, hexamethylbenzene, o-cymene, m-cymene,and p-cymene. In some embodiments, the optionally substituted arene ringis selected from benzene, mesitylene, hexamethylbenzene, and p-cymene.In certain embodiments, the optionally substituted benzene ligand isη⁶-hexamethylbenzene.

The ruthenium transfer-hydrogenation catalyst can be prepared by avariety of known methods for complexation (see, e.g., T. Ikariya et al.,Org. Biomol. Chem. (2006) 4:393-406). In some embodiments, the rutheniumtransition metal catalyst is synthesized from an (arene)Ru(X_(a))₂ dimerand an amino alcohol ligand in the presence of a base (e.g., an alkoxidebase or an amine base) and alcoholic solvent (e.g., isopropanol). First,a catalyst precursor, such as (iii-i) or (iii-j), is formed having themonodentate anionic ligand X_(a) bound to Ru:

wherein R^(a), R^(b), R^(c), R^(h), R^(i), R^(j), R^(k), R^(l), R^(m),R^(n), R^(o) and X_(a) are as defined above and herein.

Upon addition of base, such as, but not limited to, an amine base (e.g.,triethylamine) or an alkoxide base (e.g., KOiPr, NaOiPr, KOtBu, NaOtBu),the catalyst precursor can convert to the active hydrido catalyst(iii-a) or (iii-h) with concommitant formation of acetone:

wherein R^(a), R^(b), R^(c), R^(h), R^(i), R^(j), R^(k), R^(l), R^(m),R^(n), R^(o), and X_(a) are as defined above and herein.

During the transfer-hydrogenation reaction of a compound of formula (I)to form a compound of formula (II), in some embodiments, the activecatalyst can cycle between the hydrido catalyst (iii-a) or (iii-h) andthe free aminoalkoxy species (iii-k) or (iii-l), respectively:

wherein R^(a), R^(b), R^(c), R^(h), R^(i), R^(j), R^(k), R^(l), R^(m),R^(n), and R^(o) are as defined above and herein.

Thus, the term “ruthenium transfer-hydrogenation catalyst” as usedherein refers to any and all ruthenium complexes of the formulas(iii-a), (iii-h), (iii-i), (iii-j), (iii-k), and (iii-l) and theirmixtures, and all subgenuses thereof. In some embodiments, the rutheniumtransfer-hydrogenation catalyst is a mixture of any or all of (iii-i),(iii-a), and (iii-k). In certain embodiments, the rutheniumtransfer-hydrogenation catalyst is a mixture of any or all of (iii-j),(iii-h), and (iii-i).

In certain embodiments of formula (iii-i), R^(a) and R^(b) are the samegroup selected from C₁₋₆ alkyl and C₁₋₆ perhaloalkyl, or R^(a) and R^(b)are joined to form a 3-8 membered carbocyclic or heterocyclic ringsystem; R^(c) is selected from C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, aralkyl,heteroaralkyl, aryl and heteroaryl; each R^(h), R^(i), R^(j), R^(k),R^(l), and R^(m) are independently selected from hydrogen, alkyl,perhaloalkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl,heteroaryl, aralkyl, or heteroaralkyl; and X^(a) is selected from halo(e.g., iodo (I⁻), bromo (Br⁻), chloro (Cl⁻) and fluoro (F−)). In certainembodiments of formula (iii-i), R^(a) and R^(b) are the same groupselected from C₁₋₆ alkyl; R^(c) is selected from C₁₋₆ alkyl; each R^(h),R^(i), R^(j), R^(k), R^(l), and R^(m) are independently selected fromhydrogen and C₁₋₆ alkyl; and X_(a) is Cl. In some embodiments of formulaR^(a) and R^(b) are each Me, R^(c) is Et, each R^(h), R^(i), R^(j),R^(k), R^(l), and R^(m) is Me, and X_(a) is Cl.

In certain embodiments of formula (iii-k), R^(a) and R^(b) are the samegroup selected from C₁₋₆ alkyl and C₁₋₆ perhaloalkyl, or R^(a) and R^(b)are joined to form a 3-8 membered carbocyclic or heterocyclic ringsystem; R^(c) is selected from C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, aralkyl,heteroaralkyl, aryl and heteroaryl; and each R^(h), R^(i), R^(j), R^(k),R^(l), and R^(m) are independently selected from hydrogen, alkyl,perhaloalkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl,heteroaryl, aralkyl, or heteroaralkyl. In certain embodiments of formulaR^(a) and R^(b) are the same group selected from C₁₋₆ alkyl; R^(c) isselected from C₁₋₆ alkyl; and each R^(h), R^(i), R^(j), R^(k), R^(l),and R^(m) are independently selected from hydrogen and C₁₋₆ alkyl. Insome embodiments of formula (iii-k), R^(a) and R^(b) are each Me, R^(c)is Et, and each R^(h), R^(i), R^(j), R^(k), R^(l), and R^(m) is Me.

Provided herein is an achiral catalyst comprising one or more complexesof formulas (iii-a) and (iii-k):

wherein, independently for each of formulas (iii-a) and (iii-k):

each R^(a) and R^(b) are the same group selected from hydrogen, alkyl,perhaloalkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl,heteroaryl, aralkyl, or heteroaralkyl, or R^(a) and R^(b) are joined toform a 3-8 membered carbocyclic or heterocyclic ring system;

R^(c) is selected from alkyl, perhaloalkyl, alkenyl, alkynyl,carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl;and

each R^(h), R^(i), R^(j), R^(k), R^(l), and R^(m) are independentlyselected from hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl,carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl.

In some embodiments, for both formulas (iii-a) and (iii-k), R^(a) andR^(b) are each Me, R^(c) is Et, and each R^(h), R^(i), R^(j), R^(k),R^(l), and R^(m) is Me.

Provided herein is an achiral catalyst of formula (iii-i):

wherein:

each R^(a) and R^(b) are the same group selected from hydrogen, alkyl,perhaloalkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl,heteroaryl, aralkyl, or heteroaralkyl, or R^(a) and R^(b) are joined toform a 3-8 membered carbocyclic or heterocyclic ring system;

R^(c) is selected from alkyl, perhaloalkyl, alkenyl, alkynyl,carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl;and

each R^(h), R^(i), R^(j), R^(k), R^(l), and R^(m) are independentlyselected from hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl,carbocycle, heterocycle, aryl, heteroaryl, aralkyl, or heteroaralkyl;and

X_(a) is selected from iodo (F⁻), bromo (Br⁻), chloro (Cl⁻) and fluoro(F⁻).

In some embodiments, R^(a) and R^(b) are each Me, R^(c) is Et, eachR^(h), R^(i), R^(j), R^(k), R^(l), and R^(m) is Me, and X_(a) is Cl⁻.

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isgenerated by heating (hexamethylbenzene)RuCl₂ dimer and an amino alcoholin isopropanol and triethylamine. In other embodiments, the rutheniumtransfer-hydrogenation catalyst is generated by heating(hexamethylbenzene)RuCl₂ dimer and an amino alcohol in isopropanol andan alkoxide base (e.g., KOiPr, NaOiPr, KOtBu, NaOtBu). In someembodiments, KOiPr is employed in the complexation reaction.

In certain embodiments, the ruthenium transfer-hydrogenation catalyst isgenerated from hexamethylbenzene ruthenium chloride dimer and an aminoalcohol. In certain embodiments, the ruthenium transfer-hydrogenationcatalyst is generated from hexamethylbenzene ruthenium chloride dimerand a chiral amino alcohol. In certain embodiments, the rutheniumtransfer-hydrogenation catalyst is generated from hexamethylbenzeneruthenium chloride dimer and an achiral amino alcohol.

In certain embodiments, the ruthenium transition metal catalyst isprepared using about 0.1% to about 1 mol %, or about 0.25% to about 0.5%of a ruthenium halide dimer. In some embodiments, the ruthenium halidedimer is an (arene)ruthenium halide dimer, such as(hexamethylbenzene)RuCl₂ dimer. In some embodiments of the complexationreaction, the amino alcohol ligand is present in about 0.5 mol % toabout 5 mol %, about 1 mol % to about 3 mol %, or about 1 mol % to about2 mol %. In certain embodiments, the amino alcohol ligand is present inabout 3 mol %. In some embodiments, the amino alcohol ligand is ofFormula (i-a), such as (i-j). In certain embodiments, the amount of baseused in the complexation reaction is about 0.25 mol % to about 10 mol %,about 0.5 mol % to about 5 mol %, or about 0.5 mol % to about 1 mol %.In some embodiments, the amount of base used in the complexationreaction is about 5 mol %. In some embodiments, the reaction isperformed at about 25° C. to about 100° C., about 40° C. to about 80°C., or about 50° C. to 75° C. In certain embodiments, the reaction isperformed at about 50° C. In other embodiments, the reaction isperformed at about 80° C. In some embodiments, the reaction is performedfor 1 hour or 2 hours.

Several exemplary non-limiting sets of reaction parameters for thesynthesis of the ruthenium transition metal catalyst are given below inTable 5.

TABLE 5 Amino iPrOH Alcohol (vol. Parameter (Hexamethylbenzene) Ligand(i-j) KOiPr relative to Temp Set RuCl₂ Dimer (mol %) (mol %) (mol %) Rudimer) (° C.) Time (h) 1 0.5 1.5 1.5 160 ~80 2 2 0.5 2 1 100 ~50 1 30.25 1 0.5 100 ~50 1Other Reaction Conditions

In one aspect, provided herein is a process for preparing a compound offormula (II) or its pharmaceutically acceptable forms thereof from acompound of formula (I) or its pharmaceutically acceptable formsthereof, the process comprising reacting a compound of formula (I) orits pharmaceutically acceptable forms thereof with atransfer-hydrogenation catalyst in order to provide a compound offormula (II) or its pharmaceutically acceptable forms thereof.

In certain embodiments, the process further comprises a base. Exemplarybases include, but are not limited to, alkoxides (e.g., KOiPr, NaOiPr,KOtBu, NaOtBu), hydroxides (e.g., KOH, NaOH) and tertiary amines (e.g.,NEt₃). In certain embodiments, the base is an alkoxide. In certainembodiments, the base is KOiPr. In certain embodiments, the base isKOtBu. In other embodiments, the base is NaOiPr. In certain embodiments,the base is NaOtBu. In some embodiments, the base is NEt₃.

In certain embodiments, the process provides about 5 mol % to about 30mol %, about 5 mol % to about 20 mol %, about 5 mol % to about 15 mol %,or about 5 mol % to about 10 mol % of base (calculated from the molaramount of compound (I)). In certain embodiments, the process providesabout 10 mol % of base. In certain embodiments, the process providesabout 20 mol % of base. In other embodiments, the process provides about5% weight/volume of base. In some embodiments, the process providesabout 0.1 to about 0.2 (e.g., 0.2) equivalents of base based upon theamount of compound (I).

In certain embodiments, the process further comprises a hydrogen donor.Exemplary hydrogen donors include, but are not limited to, organicalcohols (e.g., methanol (MeOH), ethanol (EtOH), isopropanol (iPrOH),t-butanol (tBuOH), benzyl alcohol) and formic acid or salts thereof(e.g., amonium formate, and alkyl ammonium formates such astriethylammoniumformate (TEAF)). In certain embodiments, the organicalcohol is isopropanol. In other embodiments, the organic alcohol ismethanol. In some embodiments, the organic alcohol is t-butanol.

In some embodiments, the process comprises a mixture of a base (e.g., analkoxide base as described herein) and a hydrogen donor (e.g., anorganic alcohol as described herein). In certain embodiments, the ratioof base to hydrogen donor is 0.4 equivalents base/2 vol. hydrogen donor.In other embodiments, the ratio of base to hydrogen donor is 0.1equivalents base/10 vol. hydrogen donor. In some embodiment, the base isKOiPr and the hydrogen donor is iPrOH.

In certain embodiments, the process further comprises a solvent.Exemplary solvents include, but are not limited to, ethers (e.g.,dimethyl ether, diethyl ether, diisopropyl ether, methyltert-butylether, tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-Me-THF),1,3-dioxolane, 1,4-dioxane), hydrocarbons (e.g., benzene, toluene,xylene, mesitylene, hexanes, heptanes, cyclohexane, methylcyclohexane,acetonitrile, acetone), polar aprotic solvents (e.g., dimethylformamide,dimethylsulfoxide), halogenated solvents (e.g., dichloromethane,chloroform) or combinations thereof. In certain embodiments, the solventis an ether. In certain embodiments, the solvent is 2-methyltetrahydrofuran (2-Me-THF). In some embodiments, the solvent is selectedfrom acetonitrile, 2-methyl tetrahydrofuran (2-Me-THF), acetone, andmesitylene. In some embodiments, the solvent is mesitylene.

In certain embodiments, the process further comprises a hydrogen donorand a solvent, as described above and herein. For example, in certainembodiments, the process further comprises an organic alcohol and asolvent. In certain embodiments, the process further comprises ahydrogen donor and an ether solvent. In certain embodiments, the processfurther comprises isopropanol and 2-methyltetrahydrofuran. In certainembodiments, the process further comprises isopropanol and mesitylene.In some embodiments, the process further comprises a hydrogen donor, abase, and a solvent. For example, the process can further compriseformic acid, triethylamine and DMF.

In certain embodiments, the process further comprises a hydrogen donorand a solvent, as described above and herein, wherein the mixturecomprises about 10% to about 80%, about 20% to about 75% or about 30% toabout 70% hydrogen donor in solvent. In certain embodiments, the mixturecomprises about 40% hydrogen donor in solvent (i.e., a ratio of about2:5 hydrogen donor:solvent). In certain embodiments, the mixturecomprises about 66% hydrogen donor in solvent (i.e., a ratio of about2:1 hydrogen donor:solvent).

In certain embodiments, the process is conducted at a temperature of 0°C. to about 90° C., of about 25° C. to about 80° C., of about 0° C. toabout 50° C., of about 20° C. to about 45° C., of about 10° C. to about40° C., of about 15° C. to about 30° C., or of about 5° C. to about 20°C. In certain embodiments, the process is conducted at about roomtemperature (e.g., at a temperature of about 23° C. or about 25° C.). Insome embodiments, the process is conducted at about 80° C. In otherembodiments, the process is conducted at about 45° C. In otherembodiments, the process is conducted at about 40° C. In otherembodiments, the process is conducted at about 0° C. In someembodiments, the process is conducted at about 5° C. to about 20° C.

In certain embodiments, the process further comprises about 0.1 mol % toabout 2.0 mol %, about 0.5 mol % to about 2.0 mol %, about 0.1 mol % toabout 1.5 mol %, about 0.1 mol % to about 1.0 mol %, about 0.1 mol % toabout 0.5 mol %, or about 0.2 mol % to about 0.5 mol % of the rutheniumtransition metal catalyst (calculated from the molar amount of compound(I)). In certain embodiments, the process provides about 0.2 mol % ofthe ruthenium transition metal catalyst. In certain embodiments, theprocess provides about 0.25 mol % of the ruthenium transition metalcatalyst. in other embodiments, the process provides about 0.5 mol % ofthe ruthenium transition metal catalyst. In certain embodiments, theprocess provides about 1 mol % of the ruthenium transition metalcatalyst. In certain embodiments, the process provides about 1.5 mol %of the ruthenium transition metal catalyst.

In certain embodiments, the process further comprises removing residualruthenium from the reaction mixture once the compound of Formula (II)has formed using a scavenger. Exemplary scavengers include, but are notlimited to, silica based products from Phosphonics (SEA, STA3, POH1,SEM22, SEM26, SPM36F, SPM32 and MTCf), SiliCycle (SiliaBond-DMT,Si-Imidazole, Si-TAAcOH, Si-Diamine, Si-Triamine, Si-DMT, Si-TAAcONa,Si-Thiol and Si-Thiourea), fiber based materials from Johnson-Matthey(S-301, Smopex 111pp, Smopex 112v and Smopex 234), activated carbon(Norit E-supra) and silica gel (EMD). In certain embodiments, thescavenger is SiliaBond-DMT. In other embodiments, the scavenger isSPM32. In some embodiments, the scavenger is Si-Thiol. In someembodiments, the scavenger is selected from SEM22, SPM32, Si-Thiol,Si-DMT, and STA3.

In some embodiments, the scavenger amount is about 20 wt % to about 100wt % based on a theoretical 100% yield of the compound of Formula (II),such as about 30 to about 50 wt %. In other embodiments, the scavengeramount is about 100 wt %. In some embodiments, the scavenger amount is40 wt % and the reaction mixture is stirred with the scavenger presentfor about 10 to about 25 hours (e.g., about 20 hours). In certainembodiments, the scavenger is SPM32 at 50 c wt %, and the reactionmixture is stirred with the scavenger present at 50° C. for about 10hours.

In a non-limiting example, the synthesis of a compound of Formula (II)as described herein can be performed using about 0.25 mol % to about 2mol % (e.g., about 1 mol %) ruthenium transition metal catalyst, about 2vol. to about 20 vol. (e.g., about 10 vol.) hydrogen donor, about 0.02mol % to about 0.1 mol % (e.g., about 0.05 mol %) base, at about 0° C.to about 20° C. (e.g., about 13° C.). In some embodiments, the synthesisof a compound of Formula (II) as described herein can be performed usingabout 0.5 mol % to about 2 mol % (e.g., about 0.5 mol % or about 1 mol%) ruthenium transition metal catalyst, such as (iii-g); about 2 vol. toabout 20 vol. (e.g., about 2, 5, 6 or 10 vol.) hydrogen donor, such asiPrOH; about 0.05 equiv. to about 0.2 equiv. (e.g., about 0.1 or about0.2 equiv.) base, such as KOiPr; about 3 vol. to about 10 vol. oforganic solvent (e.g. about 5 vol.), such as 2-Me-THF; at about 5° C. toabout 25° C. (e.g., about 20° C.). In some embodiments, the reactionproceeds for about 2 to about 10 hours (e.g., about 4 or about 7 hours).

EXEMPLIFICATION

The chemical entities described herein can be synthesized according toone or more illustrative schemes herein and/or techniques well known inthe art.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure, generally within a temperature range from−10° C. to 200° C. Further, except as otherwise specified, reactiontimes and conditions are intended to be approximate, e.g., taking placeat about atmospheric pressure within a temperature range of about −10°C. to about 110° C. over a period that is, for example, about 1 to about24 hours; reactions left to run overnight in some embodiments canaverage a period of about 16 hours.

The terms “solvent,” “organic solvent,” or “inert solvent” each mean asolvent inert under the conditions of the reaction being described inconjunction therewith including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, N-methylpyrrolidone (“NMP”), pyridine and the like. Unlessspecified to the contrary, the solvents used in the reactions describedherein are inert organic solvents. Unless specified to the contrary, foreach gram of the limiting reagent, one cc (or mL) of solvent constitutesa volume equivalent.

Isolation and purification of the chemical entities and intermediatesdescribed herein can be effected, if desired, by any suitable separationor purification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography orthick-layer chromatography, or a combination of these procedures.Specific illustrations of suitable separation and isolation proceduresare given by reference to the examples hereinbelow. However, otherequivalent separation or isolation procedures can also be used.

When desired, the (R)- and (S)-isomers of the non-limiting exemplarycompounds, if present, can be resolved by methods known to those skilledin the art, for example by formation of diastereoisomeric salts orcomplexes which can be separated, for example, by crystallization; viaformation of diastereoisomeric derivatives which can be separated, forexample, by crystallization, gas-liquid or liquid chromatography;selective reaction of one enantiomer with an enantiomer-specificreagent, for example enzymatic oxidation or reduction, followed byseparation of the modified and unmodified enantiomers; or gas-liquid orliquid chromatography in a chiral environment, for example on a chiralsupport, such as silica with a bound chiral ligand or in the presence ofa chiral solvent. Alternatively, a specific enantiomer can besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer tothe other by asymmetric transformation.

The compounds described herein can be optionally contacted with apharmaceutically acceptable acid to form the corresponding acid additionsalts. Also, the compounds described herein can be optionally contactedwith a pharmaceutically acceptable base to form the corresponding basicaddition salts.

In some embodiments, disclosed compounds can generally be synthesized byan appropriate combination of generally well known synthetic methods.Techniques useful in synthesizing these chemical entities are bothreadily apparent and accessible to those of skill in the relevant art,based on the instant disclosure. Many of the optionally substitutedstarting compounds and other reactants are commercially available, e.g.,from Aldrich Chemical Company (Milwaukee, Wis.) or can be readilyprepared by those skilled in the art using commonly employed syntheticmethodology.

The discussion below is offered to illustrate certain of the diversemethods available for use in making the disclosed compounds and is notintended to limit the scope of reactions or reaction sequences that canbe used in preparing the compounds provided herein.

The present disclosure now being generally described, it will be morereadily understood by reference to the following examples, which areincluded merely for purposes of illustration and are not intended tolimit the disclosure herein.

Example 1 Preparation of Ruthenium Transfer-Hydrogenation Catalyst(iii-g)

A. Preparation of Amino Alcohol (i-j)

To a mixture of 2-amino-2-methyl-propan-1-ol (200 g, 2.2 mol, 1 equiv)and water (1 volume) was added bromoethane (489 g, 4.4 mol, 2 equiv).The mixture was stirred for 24-48 hours at 40° C., then cooled to RT.50% aqueous NaOH (1 vol) was added and then the mixture was extractedwith dichloromethane. Concentration of the organic layer in vacuo,followed by crystallization from MTBE (5 vol), afforded the aminoalcohol (i-j).

B. Preparation of Ru Amino Alcohol Catalyst (iii-g)

Into a three neck 3 L round bottom flask, equipped with Claisen adapter,temperature probe, gas inlet and outlet, condenser and heating mantle,were added (hexamethylbenzene)ruthenium chloride dimer (8.87 g, 13.27mmol, 1 mole equiv) and 2-(N-ethylamino)-2-methyl-propan-1-ol (i-j)(6.22 g, 53.1 mmol, 4 mole equiv). The flask was evacuated and refilledwith nitrogen for three times. 2-Propanol (1 L, 112 vol based on the Rudimer), degassed by sparging with argon for 30 min, was added to theflask. To the stirred suspension, potassium isopropoxide (5.0% w/v in2-PrOH, 52 ml, 27 mmol) was added at room temperature. The reactionmixture was heated to 50° C. and stirred at 50° C.±5° C. for 80 min. Theheating was turned off and the reaction was allowed to cool to roomtemperature with stirring. In this way, the catalyst[(2-N-ethylamino)-2-methyl-propan-1-ol](hexamethylbenzene)rutheniumhydride (iii-g) was prepared for use in transfer-hydrogenation of acompound of formula (I).

Example 2 Transfer Hydrogenation of a Compound of Formula (I-a)

A. Preparation of a Compound of Formula (II-a)

A solution of the ketone (I-a) (1.825 kg, 3.54 mol) in 9.1 L 2-MeTHF wasadded to a 50 L jacketed reactor equipped with mechanical stirrer, 1000mL addition funnel with ¼″ PTFE connecting tube (with a shutoff valvein-between) to a 3 L catalyst vessel, The solution was diluted with2-PrOH (11 L). Potassium isopropoxide (5% w/v in 2-PrOH, 354 mmol, 700mL) was added. The mixture was sparged with argon for 60 min. Thecatalyst (iii-g) (0.5 mole %, 11.04 g, 26.5 mmol) was added via theaddition funnel. The mixture was stirred for 90 min under argonatmosphere at room temperature. An HPLC sample was prepared by removing10 μl of the reaction mixture and diluting it into ACN (1 mL) The HPLCshowed less than 1% of the starting material remained. PhosphonicS SPM32resin (913.5 g, 50 wt % based on starting material) was added to thereaction mixture. The reactor was equipped with a reflux condenser, andthe slurry was stirred for 18 h at 50° C. The mixture was cooled to roomtemperature (19° C.) and the scavenger was removed by filtration on aBuchner filter. The cake comprising (II-a) was washed with 2-MeTHF (2volumes based on product 100% yield).

In order to remove the 2-PrOH from the isolated cake, five solventchases with 2-Me-THF were carried out prior to the crystallization. A 50L jacketed reactor was equipped with mechanical stirrer, distillationapparatus and connected to Huber. The reactor was marked for 5 vol and20 vol solution. The solution of (II-a) was charged to the reactor.Vacuum was applied and the solution was heated to begin the distillation(40±5° C.). The solution was concentrated to 5 vol (9 L based on II-a).2-Me-THF (15 vol, 27.5 L) was added, and vacuum was applied beforerestarting the heating. The solution was concentrated to 5 vol (9 L) byvacuum distillation (40±5° C.). The charging of 2-Me-THF (15 vol, 27.5L) and concentration to 5 volumes was performed as described above fourmore times. The solution (9 L in 2-Me-THF) was added to the reactor.Acetonitrile (11 L, 6 volumes) was charged at 20±5° C. with stirring.The mixture was stirred at 20±5° C. for 60 min to initiate thecrystallization. Water was added over 60 min (22 L, 12 vol) at 20±5° C.,and then the mixture was stirred for 2 hours. The product (II-a) wasisolated by filtration on Buchner filter. The cake was washed with 2/1water/ACN (2 vol, 60 mL). The cake was kept on the filter for 60 min Theproduct was dried in a vacuum oven at 70° C. to afford (S)-(II-a) as a99:1 β:α ratio of diastereomers.

B. Ru Scavenger Evaluation 1

To the mixture attained after stirring the components for 90 minutes atroom temperature, 1 wt equivalent of the following scavengers was addedand the resulting mixture was stirred for 18 h at 50° C. The mixture wasthen cooled to room temperature and filtered. The filtrate wasconcentrated in vacuo and the residue evaluated for Ru content byICP-OES as shown in Table 6.

TABLE 6 Scavenger Residual Ru None 3211 ppm SEM26  16 ppm SPM32  19 ppmMTCf  53 ppm JM S-301 4195 ppm JM Smopex 111pp 2704 ppm JM Smopex 112v1048 ppm JM Smopex 234  229 ppm Norit  570 ppm None 1654 ppmSi-Imidazole  357 ppm Si-Diamine  653 ppm SiliaBond DMT   8 ppmSi-TAAcONa  316 ppm Si-Thiol   7 ppm Si-Thiourea  75 ppm Si-Triamine 639 ppm SPM36f  22 ppm

C. Ru Scavenger Evaluation 2

To a mixture of 500 mg of (II-a) where R¹=Bn, 1 wt equivalent of thefollowing scavengers was added at 20° C. and the resulting mixture wasstirred for 17 h at 50° C. The mixture was then cooled to roomtemperature and filtered. The filtrate was concentrated in vacuo and theresidue was evaluated for Ru content by ICP-MS as shown in Table 7.

TABLE 7 Scavenger Residual Ru None  1500 ppm SEM22  5.2 ppm SPM32  4.1ppm STA3  46.1 ppm Si-Thiol  2.4 ppm Si-DMT  4.1 ppm

D. Ru Scavenger Evaluation 3

Using the procedure of Example 2C, the following scavengers wereevaluated for residual Ru at three time points as shown in Table 8.

TABLE 8 Test Test Test Test Test Test Parameters D.1 D.2 D.3 D.4 D.5 D.6Scale (g of 20 20 5 5 5 ⁵ (II-a)) Scavenger SPM32 SPM32 SPM32 Si-ThiolSi-Thiol Si-Thiol Amt. 0.3 0.3 0.5 0.2 0.3 0.5 Scavenger (wt. equiv.)Temp. (° C.) 20 50 50 50 50 50 Residual Ru 43.0/5  37.5/2 8/4  33/4 15/4  ⁹/4  (ppm)/time point 1 (h) Residual Ru 36.4/10 25.0/6 5/10 21/108/10 5/10 (ppm)/time point 2 (h) Residual Ru 30.6/19  17.8/16 4/18 15/186/18 4/18 (ppm)/time point 3 (h)

E. Reaction Scale Evaluation

The Example 2A procedure was performed using the following amounts ofstarting material (I-a) where R¹ is Bn and allowed to react with the Rucatalyst (iii-g) for the given reaction times. The diastereoselectivityof the resulting compound (II-a) is shown in Table 9.

TABLE 9 Reaction Reaction time (II-a) scale with 1 mole % β/α (I-a) Rucatalyst ratio  37 g  60 min 99.3/0.7  60 g  90 min 99.3/0.7  50 g 420min 99/1  39 g  90 min 99/1  183 g 150 min 98.7/1.3 1958 g  90 min 99/1

Example 3 Hydrogenation of a Compound of Formula (I-a) Using HCO₂H:Et₃N

A. General Reaction Conditions

A Schlenk flask was charged with (I-a, R¹=Bn) (0.5 g, 0.969 mmol) and(S,S)TsDPENRuCl₂(p-cymene) (15.7 mg, 0.025 mmol). The flask was putunder argon, and 16 mL triethylamine was added, followed by 4 mL offormic acid. This mixture was heated to 75° C. for 24 h. The reactionwas then analyzed by HPLC after 24 h indicating a (S)-(II-a) β/α ratioof 80:20.

B. Reaction Solvent Evaluation

A mixture of 140 mg of (I-a, R¹=Cbz) and 3.2 mg(S,S)TsDPENRuCl₂(p-cymene) was prepared in 1 mL 2-MeTHF and stirreduntil it became homogenous. To each of five vials was added 200 μL ofthis solution, to give five vials total with 28 mg of (I-a, R¹=Cbz) and0.63 mg (S,S)TsDPENRuCl₂(p-cymene) in 200 μL, 2-MeTHF. Then, to eachvial was added 800 μL of a solvent as shown in Table 10. 100 μL of a 5:2molar ratio solution of folinic acid:triethylamine was added to eachvial, and the mixture was stirred for 20 h at RT. The resulting β/αdiastereomeric ratio of the product (II-a, R¹=Cbz) was determined byHPLC.

TABLE 10 (II-a, R¹ = Cbz) Vial Solvent β/α ratio 1 2-MeTHF 91:9  2 DMF95:5  3 MeOH 90:10 4 iPrOH 73:27 5 toluene 83:17

Example 4 Transfer-Hydrogenation of a Compound of Formula (I-g)

Using an analogous procedure to Example 2A, except ketone (I-g) wassubstituted for ketone (I-a), the Ru catalyzed transfer-hydrogenationafforded alcohol (R)-(II-g) as a 1:99 β:α ratio of diastereomers. LCMS:(M+H) 518.36.

Example 5 Transfer-Hydrogenation of a Compound of Formula (I-a) Using aChiral Ru Catalyst

Using an analogous procedure to Example 2A, except that 20 mol % NaOiPrin iPrOH was used in place of 5% KOiPr in iPrOH, the following Ru chiraltransfer-hydrogenation catalysts 1-7 were evaluated for reduction of(I-a) to (II-a) as shown in Table 11. The β-hydroxy isomer is (S)-(II-a)while the α-hydroxy isomer is the diastereomeric (R)-(II-a).

TABLE 11 Catalyst (II-a) β:α ratio 1. (S,S)TsDPEN-RuCl(p-cymene) (R¹ =Cbz) 92:8  2. ((1R,2S)aminoindanol)RuCl(p-cymene) (R¹ = Cbz) 63:27 3.((1S,2R)aminoindanol)RuCl(p-cymene) (R¹ = Cbz) 51:49 4.(Ph₃P)RuCl₂((+)-(R)-Fe-oxazoline) (R¹ = Bn) 44:56 5.(Ph₃P)RuCl₂((−)-(S)-Fe-oxazoline) (R¹ = Bn) 52:48 6.((S,R)JOSIPHOS)RuCl₂(DMF)_(n) (R¹ = Cbz)  4:96 7.((R,S)JOSIPHOS)RuCl₂(DMF)_(n) (R¹ = Cbz)  4:96

Example 6 Transfer-Hydrogenation of a Compound of Formula (I-a) Using aChiral Ru Bis-Phosphonite Catalyst

Into a three-neck 500 ml round bottom flask, equipped with Claisenadapter, temperature probe, gas inlet and outlet, condenser and heatingmantle, were added (p-cymene)ruthenium chloride dimer 43.3 mg, 0.071mmol, 0.020 mole equiv) and(11bS,11′bS)-4,4′-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis-dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin(302 mg, 0.36 mmol, 0.10 mole equiv). The flask was evacuated andrefilled with nitrogen for three times. 2-Propanol (238 ml, 160 volbased on the Ru dimer), degassed by sparging with argon for 30 min, wasadded to the flask. The reaction mixture was heated to 80° C. To thestirred suspension, potassium t-butoxide (1 M in 2-PrOH, 3.6 ml, 3.6mmol, 1 equiv) was added and the reaction was stirred at 40° C. forhours. A solution of the ketone (I-a) 1.83 g, 3.6 mmol, 1 equivalent) in18 ml iPrOH was added and the mixture was stirred for 64 hours at 40° C.HPLC analysis of the reaction mixture indicated that the product(S)-(II-a) was a 97:3 β:α ratio of diastereomers.

This procedure was repeated with 70 volumes of iPrOH based on the Rudimer, affording (S)-(II-a) as a 95:5 β:α ratio of diastereomers, and 35volumes of iPrOH based on the Ru dimer, affording (S)-(II-a) as an 82:18β:α ratio of diastereomers.

Example 7 Transfer-Hydrogenation of a Compound of Formula (I-a) Using aRu-Ephedrine Catalyst

A. Exemplary Formation of Ru-Ephedrine Catalysts

To a mixture of (mesitylene)ruthenium chloride dimer (60.6 mg, 0.104mmol, 0.5 mole equiv) and (1S,2R)-ephedrine HCl (62.7 mg, 0.311 mmol,1.5 mole equiv) was added degassed iPrOH (14.8 ml). To the stirredsuspension, Et₃N (300 μl, 2.15 mmol) was added to give a 4.01 mg Ru/mlsolution. The reaction mixture was heated to 85° C. and stirred at 85°C. for two hours. The heating was turned off and the reaction allowed tocool to room temperature with stirring. In this way, the(mesitylene)RuCl-ephedrine catalyst (10) was prepared for use in thetransfer-hydrogenation of a compound of formula (I). In addition, Ruchloride dimers having different arene ligands were used to prepare thefollowing (arene)RuCl-ephedrine catalysts (11) to (17) in an analogousmanner:

B. Transfer-Hydrogenation of a Compound of Formula (I-a) Using RuCatalysts 11-17

To (I-a) (10.00 g, 19.4 mmol) was added iPrOH (100.0 mL, 10.0 vol) andthe mixture was stirred. RuCl-ephedrine catalyst (10) (7.1 mL, 28.5 mgRu, 0.0488 mmol, 0.25 mol % Ru dimer) was added, followed by 1.94 mL of1M KOtBu in tBuOH (1.94 mmol, 10 mol %). The mixture was stirred for 45min at room temperature. Then, EtOAc (135 mL) was added, followed by 20mL of 5-6 N HCl in isopropanol, and the mixture was stirred for 16 h.After concentrating in vacuo to a net weight of 5 weights, filteringthrough a fritted funnel, and further concentration, (S)-(II-a) wasisolated as its HCl salt with a β:α diastereoselectivity ratio of 98:2by HPLC analysis.

Using analogous procedures to Examples 7A and 7B, compounds of Formula(II-a) were prepared with Ru-ephedrine catalysts 10, 12-15, and 17 withthe diastereoselctivity indicated in Table 12.

TABLE 12 Catalyst: (II-a)β:α Catalyst: (II-a)β:α ratio with 1R,2S ratiowith 1S,2R mol % Arene ephedrine ligand ephedrine ligand Ru usedmesitylene (11): — (10): 96.5:3.5 0.5% hexamethylbenzene (12): 96:4(13): 98.8:1.2 1.5% p-cymene (14): 75:25 (15): 85:15 0.5% benzene (16):— (17): 52:48 0.5%

B.1 Effect of Temperature and Catalyst Loading on theDiastereoselectivity of a Compound of Formula (II-a)

Using an analogous procedure to Example 7B, Ru-(1S,2R)-ephedrinetransfer-hydrogenation catalysts having either mesitylene (10) orhexamethylbenzene (13) arene ligands were employed to determine theeffect of temperature and catalyst loading (mol % based on amount of(I-a)) on diastereoselectivity in the transfer-hydrogenation of acompound of Formula (I-a) where R¹ is Bn. The resultingdiastereoselectivity of compounds of Formula (II-a) are summarized inTable 13.

TABLE 13 Ru Catalyst (II-a) Loading Temperature β:α Arene (mol %) (° C.)ratio mesitylene (10) 0.5% 23 96.5:3.5  mesitylene (10) 0.5% 0 97:3 hexamethylbenzene (13) 0.2% 45 89:11 hexamethylbenzene (13) 0.5% 2398.8:1.2  hexamethylbenzene (13) 0.5% 0 —

Example 8 Transfer-Hydrogenation of a Compound of Formula (I-a) Using aChiral Ru Catalyst

Using a procedure analogous to Example 7A, the following chiral Rutransfer-hydrogenation catalysts were prepared (Formulas 18 to 92) usingthe (arene)ruthenium chloride dimer and ligand given in Table 14. Usinga procedure analogous to Example 7B, these Ru transfer-hydrogenationcatalysts were used to reduce a ketone of Formula (I-a) where R¹ is Bn.The diasteroselectivity of the resulting alcohol of Formula (II-a) isgiven in Table 14.

TABLE 14 (II-a) β/ Formula Arene Ligand α ratio (18) benzene

45/55 (19) benzene

44/56 (20) benzene

39/61 (21) benzene

38/62 (22) benzene

38/62 (23) benzene

35/65 (24) benzene

28/72 (25) benzene

30/70 (26) benzene

43/57 (27) benzene

48/52 (28) benzene

54/46 (29) benzene

51/49 (30) benzene

45/55 (31) benzene

50/50 (32) benzene

44/56 (33) benzene

39/61 (34) benzene

43/57 (35) benzene

36/64 (36) p-cymene

65/35 (37) p-cymene

71/29 (38) p-cymene

46/54 (39) p-cymene

27/73 (40) p-cymene

64/36 (41) p-cymene

37/63 (42) p-cymene

58/42 (43) p-cymene

48/52 (44) p-cymene

70/30 (45) p-cymene

71/29 (46) p-cymene

48/52 (47) p-cymene

47/53 (48) p-cymene

50/50 (49) p-cymene

49/51 (50) p-cymene

64/36 (51) p-cymene

55/45 (52) p-cymene

80/20 (53) p-cymene

85/15 (54) p-cymene

71/29 (55) mesitylene

66/34 (56) mesitylene

68/32 (57) mesitylene

67/33 (58) mesitylene

67/33 (59) mesitylene

62/38 (60) mesitylene

79/21 (61) mesitylene

75/25 (62) mesitylene

84/16 (63) mesitylene

67/33 (64) mesitylene

93/7  (65) mesitylene

81/19 (66) mesitylene

80/20 (67) mesitylene

70/30 (68) mesitylene

69/31 (69) mesitylene

25/75 (70) mesitylene

57/43 (71) mesitylene

51/49 (72) mesitylene

63/37 (73) mesitylene

58/42 (74) hexamethyl- benzene

89/11 (75) hexamethyl- benzene

91/9  (76) hexamethyl- benzene

83/17 (77) hexamethyl- benzene

75/25 (78) hexamethyl- benzene

86/14 (79) hexamethyl- benzene

45/55 (80) hexamethyl- benzene

91/9  (81) hexamethyl- benzene

86/14 (82) hexamethyl- benzene

95/5  (83) hexamethyl- benzene

97/3  (84) hexamethyl- benzene

68/32 (85) hexamethyl- benzene

67/33 (86) hexamethyl- benzene

92/8  (87) hexamethyl- benzene

89/11 (88) hexamethyl- benzene

88/12 (89) hexamethyl- benzene

97/3  (90) hexamethyl- benzene

81/19 (91) hexamethyl- benzene

93/7  (92) hexamethyl- benzene

89/11

Example 9 Transfer-Hydrogenation of a Compound of Formula (I-a) Using anAchiral Ru Catalyst

Using an analogous procedure to Example 1B, the following achiral Rutransfer-hydrogenation catalysts (93, iii-g, iii-m-iii-y) were preparedusing an achiral ligand and an (arene)dichlororuthenium dimer. Thetransfer-hydrogenation reactions of a compound of Formula (I-a) where R¹is Bn with these catalysts to afford a compound of Formula (II-a) wereperformed using an analgous procedure to Example 2A, except that the Rucatalyst loading was 1 mol % or 2 mol %. The diasteroselectivity of theresulting compounds of Formula (II-a) is given in Table 14.

TABLE 14 Formula Arene Ligand (II-a) β:α ratio (93) mesitylene

75:25 iii-g hexamethylbenzene

99.1:0.9  iii-m mesitylene

59:41 iii-n mesitylene

90:10 iii-o mesitylene

55:45 iii-p mesitylene

56:44 iii-q mesitylene

40:60 iii-r mesitylene

60:40 iii-s hexamethylbenzene

96:4  iii-t hexamethylbenzene

94:6  iii-u hexamethylbenzene

52:48 iii-v hexamethylbenzene

98.7:1.3  iii-w hexamethylbenzene

91:9  iii-x p-cymene

82:18 iii-y benzene

37:63

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments described herein. Such equivalents are intended to beencompassed by the following claims.

What is claimed is:
 1. A process for preparing a compound of formula(II-a):

or a pharmaceutically acceptable form thereof; from a compound offormula (I-a):

or a pharmaceutically acceptable form thereof; wherein: R¹ is H or anitrogen protecting group; the process comprising reacting a compound offormula (I-a) or a pharmaceutically acceptable form thereof with achiral ruthenium transfer-hydrogenation catalyst of formulaRuClAr(chiral amino alcohol) or RuHClAr(chiral amino alcohol), whereinAr represents a substituted benzene ligand selected from mesitylene,cymene and hexamethylbenzene and chiral amino alcohol represents achiral amino alcohol bidentate ligand selected from ephedrine,pseudoephedrine, 2-methylaminocyclohexanol, propranolol,1-amino-2-indanol, and prolinol, in the presence of an organic alcoholhydrogen donor selected from the group consisting of methanol, ethanol,isopropanol, and t-butanol under conditions effective to provide asubstantially enantiomerically pure compound of formula (II-a) or apharmaceutically acceptable form thereof in at least about 85% weightpercent relative to an enantiomer having an (R)-stereochemicalorientation at the ring carbon atom that is directly attached to thehydroxyl group.
 2. The process according to claim 1, effective to format least about 90% by weight of the compound of formula (II-a) relativeto its α- or (R)-isomer.
 3. The process according to claim 1, whereinthe ruthenium transfer-hydrogenation catalyst comprises a chiralephedrine ligand.
 4. The process according to claim 1, wherein thechiral amino alcohol ligand is selected from chiral2-methylaminocyclohexanol, propranolol, 2-amino-1-indanol, and prolinol.5. The process of claim 3, wherein the chiral amino alcohol ligand is(1S,2R)ephedrine, (1R,2S)ephedrine, (+)-(1S,2S)pseudoephedrine, or(31)-(1R,2R) pseudoephedrine.
 6. The process according to claim 1,wherein Ar is hexamethylbenzene.
 7. The process according to claim 6,wherein the ruthenium transfer-hydrogenation catalyst is generated byreaction of (hexamethylbenzene)ruthenium chloride dimer and a chiralamino alcohol selected from ephedrine, pseudoephedrine,2-methylaminocyclohexanol, propranolol, 1-amino-2-indanol, and prolinol.8. The process according to claim 1, wherein the reacting step iscarried out in the presence of base.
 9. The process according to claim8, wherein the base is an alkoxide.
 10. The process according to claim1, further comprising a ruthenium transfer-hydrogenation catalyst offormula RuAr(chiral amino alcohol), wherein Ar and chiral amino alcoholare as defined in claim
 1. 11. The process according to claim 2, whereinthe ruthenium transfer-hydrogenation catalyst comprises one or more ofRuHCl(mesitylene)[(1S,2R)-ephedrine] (10),RuHCl(hexamethylbenzene)[(1R,2S)-ephedrine] (12),RuHCl(hexamethylbenzene)[(1S, 2R)-ephedrine] (13),RuHCl(mesitylene)[(1R,2S)2-methylaminocyclohexanol] (64),RuHCl(hexamethylbenzene)[R-propranolol] (75),RuHCl(hexamethylbenzene)[1S,2R-cis-1-amino-2-indanol] (80),RuHCl(hexamethylbenzene)[(1S,2S)2-methylaminocyclohexanol] (82),RuHCl(hexamethylbenzene)[(1R,2S)2-methylaminocyclohexanol] (83), andRuHCl(hexamethylbenzene)[D-prolinol] (86).
 12. The process according toclaim 1, wherein the ruthenium transfer-hydrogenation catalyst isselected from RuHCl(mesitylene)[(1S, 2R)-ephedrine] (10),RuHCl(hexamethylbenzene)[(1S,2R)-ephedrine] (13),RuHCl(hexamethylbenzene)[(1R,2S)-ephedrine] (12),RuHCl(p-cymene)[(1S,2R)-ephedrine] (15),RuHCl(mesitylene)[(1R,2S)2-methylaminocyclohexanol] (64),RuHCl(hexamethylbenzene)[(1R,2S)2-methylaminocyclohexanol] (83),RuHCl(hexamethylbenzene)[(1S,2S)2-methylaminocyclohexanol] (82),RuHCl(hexamethylbenzene)[R-propranolol] (75),RuHCl(hexamethylbenzene)[S-propranolol] (74),RuHCl(hexamethylbenzene)[1R,2S-cis-1-amino-2-indanol] (81),RuHCl(hexamethylbenzene)[D-prolinol] (86),RuHCl(hexamethylbenzene)[1S,2R-cis-1-amino-2-indanol] (80), andRuHCl(hexamethylbenzene)[L-prolinol] (87).
 13. The process according toclaim 2, where R¹ is selected from H, benzyl, and —CO₂R¹⁶ where R¹⁶ isselected from t-butyl and benzyl.
 14. The process of claim 13, whereinR¹ is —CO₂R¹⁶ and R¹⁶ is t-butyl.
 15. The process of claim 13 wherein R¹is —CO₂R¹⁶ and R¹⁶ is benzyl.
 16. The process of claim 1, where theorganic alcohol is isopropanol.
 17. The process of claim 1, wherein thereacting step further includes a solvent.
 18. The process of claim 17,where the solvent is an ether.
 19. The process of claim 1, wherein thecompound of formula (II-a) or a pharmaceutically acceptable form thereofis formed in enantiomeric excess of about 80% or more.